Quilomicrons

NU35CH06-Lewis ARI 6 May 2015 11:15
Review in Advance first posted online

V I E W
E on May 13, 2015. (Changes may
R
still occur before final publication
S
online and in print.)
C E
I N
A
D V A
New Insights into the

Regulation of Chylomicron
Production
Access provided by Yale University - Law Library on 05/15/15. For personal use only.
Satya Dash,1,2 Changting Xiao,1,2

Annu. Rev. Nutr. 2015.35. Downloaded from www.annualreviews.org
Cecilia Morgantini,1,2 and Gary F. Lewis1,2

1
Departments of Medicine and Physiology and the Banting and Best Diabetes Center,
University of Toronto, Toronto, Ontario, M5G 2C4 Canada; email: [email protected]
2
Division of Endocrinology, Department of Medicine, University of Toronto, Toronto,
Ontario, M5G 2C4 Canada
Annu. Rev. Nutr. 2015. 35:6.1–6.30 Keywords

The Annual Review of Nutrition is online at chylomicron, apolipoprotein B-48, triglyceride-rich lipoprotein, diabetic
nutr.annualreviews.org
dyslipidemia, atherosclerosis
This article’s doi:
10.1146/annurev-nutr-071714-034338 Abstract
Copyright c 2015 by Annual Reviews. Dietary lipids are efficiently absorbed by the small intestine, incorporated
All rights reserved
into triglyceride-rich lipoproteins (chylomicrons), and transported in the cir-
culation to various tissues. Intestinal lipid absorption and mobilization and
chylomicron synthesis and secretion are highly regulated processes. Elevated
chylomicron production rate contributes to the dyslipidemia seen in com-
mon metabolic disorders such as insulin-resistant states and type 2 diabetes
and likely increases the risk for atherosclerosis seen in these conditions. An
in-depth understanding of the regulation of chylomicron production may
provide leads for the development of drugs that could be of therapeutic
utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron
secretion is subject to regulation by various factors, including diet, body
weight, genetic variants, hormones, nutraceuticals, medications, and emerg-
ing interventions such as bariatric surgical procedures. In this review we
discuss the regulation of chylomicron production, mechanisms that underlie
chylomicron dysregulation, and potential avenues for future research.
6.1
Changes may still occur before final publication online and in print
Contents
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2
2. OVERVIEW OF DIETARY LIPID ABSORPTION AND CHYLOMICRON
ASSEMBLY, SECRETION, AND CLEARANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3
2.1. Absorption of Dietary Triglyceride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3
2.2. Cholesterol Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4
2.3. Triglyceride Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6
2.4. Chylomicron Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6
2.5. Chylomicron Clearance from the Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7
3. REGULATION OF CHYLOMICRON PRODUCTION . . . . . . . . . . . . . . . . . . . . . . . 6.8
3.1. Nutritional Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8
3.2. Hormonal, Local, and Circulating Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.11

3.3. Pharmacological Agents, Nutraceuticals, and Other Treatments . . . . . . . . . . . . . . 6.13
3.4. Circadian Regulation of Chylomicron Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15
4. THE GUT AS A LIPID STORAGE ORGAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.16

5. PLASMA CHYLOMICRON CONCENTRATION IN INSULIN
RESISTANCE AND TYPE 2 DIABETES AND ITS POTENTIAL
ROLE IN ATHEROSCLEROSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.17
5.1. Chylomicrons in Insulin Resistance and Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . 6.17
5.2. Chylomicrons and Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.17
6. GENETIC CONDITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18
6.1. Monogenic Conditions with Increased Circulating Chylomicrons . . . . . . . . . . . . . 6.18
6.2. Common Genetic Variants Associated with Increased Plasma Triglycerides . . . 6.19
6.3. Monogenic Causes of Hypotriglyceridemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19
7. FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20
7.1. Gut Microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20
7.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20
7.3. Neural Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20
7.4. The Physiological Role and Regulation of Enteral Lipid Storage . . . . . . . . . . . . . . 6.20
8. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20
1. INTRODUCTION
Ingested triglyceride (TG) is hydrolyzed in the proximal intestinal lumen by lipases to produce
fatty acids and monoacylglycerols (MAGs). These products are subsequently absorbed across the
brush border of enterocytes, where they are reesterified to diacylglycerides (DAGs) and TGs (116).
TGs are conjugated with apolipoprotein B48 in the enterocyte endoplasmic reticulum and Golgi
to form chylomicrons, which are released into the circulation via the lymphatic system (130, 173).
In the fasted state enterocytes secrete smaller, lipid-poor chylomicron particles. Postprandially,
there is a relatively small increase in the number of chylomicron particles secreted, with a very
large increase in the TG and cholesteryl ester content per particle, which greatly enlarges particle
size (59).
Although the major determinant of chylomicron production is dietary fat ingestion, a relatively
TG: triglyceride
underappreciated aspect of chylomicron production is that it is a highly regulated process, with
paracrine and systemic factors affecting production rates beyond fat ingestion (173). Furthermore,
although digestion, absorption, and incorporation of dietary fat into chylomicrons is a highly
6.2 Dash et al.
efficient and rapid process, the gut is capable of storing dietary lipid in the cytosol of enterocytes
and possibly the lacteals for several hours and subsequently mobilizing and releasing this stored
lipid as chylomicrons many hours after a meal in response to various stimuli (22, 30, 44, 130).
FABPpm: fatty
Here we provide an overview of the incorporation of dietary fat into chylomicrons and their acid–binding protein
subsequent release into the circulation. In addition, we review recent data from animal and human plasma membrane
studies, identifying regulators of chylomicron production as well as factors affecting storage and FATP4: fatty acid
subsequent release of enteral lipids. We also discuss conditions and disease states such as insulin transport protein 4
resistance and type 2 diabetes, in which increased chylomicron production contributes to the CD36: cluster
typical dyslipidemia of these conditions and potentially accelerates atherosclerotic cardiovascular determinant 36
disease. Finally, we provide a summary of our current knowledge and future directions for research I-FABP: intestinal
in the field. fatty acid–binding
protein
2. OVERVIEW OF DIETARY LIPID ABSORPTION AND CHYLOMICRON

ASSEMBLY, SECRETION, AND CLEARANCE
2.1. Absorption of Dietary Triglyceride

Dietary TG is solubilized in the duodenum and proximal jejunum by the action of bile acid mi-
celles and is digested by lingual, gastric, and pancreatic lipases to yield monoacylglycerol and fatty
acid, which are absorbed by the enterocytes in the small intestine (Figure 1). The absorption of
fatty acid and monoacylglycerol is highly efficient, with absorption of more than 95% of ingested
dietary lipid in vivo (116). Although absorption of monoacylglycerol and fatty acid likely occurs
by passive diffusion across a concentration gradient, various transporters may promote enterocyte
uptake of luminal long-chain fatty acid (LCFA) and serve important signaling functions. In vitro
studies have implicated the fatty acid–binding protein plasma membrane (FABPpm) (149) and fatty
acid–transport protein 4 (FATP4) (146), and in vivo studies have implicated fatty acid translo-
case/cluster determinant 36 (FAT/CD36) (106) (Figure 2). In addition, the plasma membrane
protein caveolin can facilitate fatty acid absorption both in vitro and in vivo, potentially by inter-
acting with CD36 (116, 129, 140). However, the presence of these fatty acid transporters is not
absolutely necessary for luminal LCFA absorption. Treatment of jejunal explants with FABPpm
antisera only modestly reduces LCFA uptake (149). FATP4 knockdown reduces fatty acid uptake
by freshly isolated enterocytes in vitro (146), a finding replicated in enterocytes isolated from
heterozygous FATP4 knockout mice (49). Furthermore, there is no evidence of fat malabsorption
in mice treated with FATP4 inhibitors (10) or in heterozygous FATP4 knockout mice (homozy-
gosity for FATP4 is embryonically lethal) (49). In CD36 knockout mice, lipid absorption in the
proximal intestine is impaired (105). No major lipid malabsorption phenotype is seen, however,
likely due to CD36-independent compensatory mechanisms in the distal gut (105). Similarly, in
CD36-deficient humans, there is no evidence of lipid malabsorption (92). To date no specific
transporters have been identified for monoacylglycerol.
Within the enterocyte, cytoplasmic fatty acid–binding proteins (FABPcs) participate in intra-
cellular transport of LCFAs (Figure 2). FABP-2 [intestine-specific FABP (I-FABP)] is expressed
in the small intestine, associates with apical LCFA in a 1:1 ratio, and is thought to deliver these
LCFAs to intracellular membranes such as the ER by a direct collision interaction to initiate TG
synthesis in vitro (109). A human genetic variant in FABP-2, in which an alanine at codon 54 is
substituted by a threonine, is associated with increased plasma TG (2), insulin resistance (7), and
weight gain (62). This may be due to enhanced affinity for LCFA (7). However, FABP-2 knockout
mice demonstrate no lipid malabsorption, which suggests that this protein is not essential for
intestinal lipid absorption. Indeed, male FABP-2 knockout mice have higher body weights and
www.annualreviews.org • Regulation of Chylomicron Production 6.3
Glycerol
phosphate pathway
Dietary glucose Glucose
sn Glycerol-3-phosphate
GPAT 3, 4
FA CoA
Lysophosphatidic acid
Fatty Fatty AGPAT 1–5

acid acid FA CoA
FATP4
Phosphatidate
Dietary +
lipid Lipolysis LIPIN 1–3
FA CoA
Monoacylglycerol Monoacylglycerol Diacylglycerol

MGAT
DGAT 1, 2
FA CoA
Monoacylglycerol
phosphate pathway Triacylglycerol
Figure 1
Triglyceride synthesis in the enterocyte. The monoacylglycerol pathway: This pathway contributes to approximately 75–80% of
triglyceride synthesis within enterocytes, with the rest coming from the glycerol phosphate pathway. Dietary triglyceride is hydrolyzed
to fatty acid and monoacylglycerol, both of which are absorbed across the intestinal brush border membrane. Fatty acid is converted to
fatty acyl CoA by FATP4. Fatty acyl CoA and monoacylglycerol can be converted to diacylglycerol, catalyzed by the enzyme MGAT,
which can be further converted to triacylglycerol by the enzyme DGAT. Glycerol phosphate pathway: Triacylglycerol can also be
synthesized from glucose and fatty acyl CoA. sn Glycerol-3-phosphate, generated by glucose, is sequentially converted to
lysophosphatidic acid, phosphatidate, and diacylglycerol by the addition of fatty acyl CoA catalyzed by GPAT, AGPAT, and lipin,
respectively. Diacylglycerol is converted to triacylglycerol as described above. Abbreviations: AGPAT, 1-acyl-sn-glycerol-3-phosphate
acyltransferase; CoA, coenzyme A; DGAT, diacylglycerol acyltransferase; FA, fatty acid; FATP4, fatty acid–transport protein 4; GPAT,
glycerol-3-phosphate:acyl-CoA acyltransferase; MGAT, monoacylglycerol acyltransferase. Figure adapted with permission from Pan &
Hussain 2012. Biochim. Biophys. Acta 1821:727–35 (116).
plasma TG concentrations (158). FABP-1 [liver-specific FABP (L-FABP)] is expressed in the liver,
small intestine, and kidney (109). Each FABP-1 protein interacts with two LCFAs and transports
them by aqueous diffusion in vitro. FABP-1 interacts with plasma membrane proteins and has
been proposed to act as a cytoplasmic reservoir for fatty acid assimilation (109) and transport of
nascent chylomicrons from the ER to the golgi in the form of prechylomicron transfer vesicle
(PCTV) (107) in vitro. FABP-1 knockout mice have increased TG retention within enterocytes,
with reduced TG secretion, and are protected against diet-induced obesity (108).
L-FABP: liver fatty

acid–binding protein 2.2. Cholesterol Absorption
PCTV: Dietary cholesterol ester is hydrolyzed to free cholesterol and fatty acid, with absorption of fatty
prechylomicron
acid as described above in Section 1.1. Free cholesterol absorption and delivery to the ER are
transport vesicle
facilitated by the Niemann-Pick C1-like 1 receptor in vitro, a target of the cholesterol absorption
inhibitor therapeutic agent ezetimibe (3, 134) (Figure 2). Free and reesterified (esterified by acyl
CoA:cholesterol acyl transferase enzyme 2) cholesterol is transferred to nascent apolipoprotein
6.4 Dash et al.
Free fatty acids Cholesterol Cholesterol

efflux
Diffusion SR-B1
FATP4 NPC1L1 ABCG5
FABpm ABCG8
CD36
Brush border
membrane
FA FC
I-FABP
L-FABP ACAT2
FA Endoplasmic
TG
reticulum
TG
TG CE
CE Budding
B48 CMpre
MTP MTP B48 TG (L-FABP)

A4
CMpri
B48 apoAI
A4
CE
CE B48 TG
B48 TG CMpre Fusion
Golgi (Sar1b, SNARE) A4
Sar1b
PCTV
VAMP7
CE
B48 TG
Basolateral membrane
ABCA1
Lymph
apoAI HDL
CE
B48 TG
Figure 2
Chylomicron assembly and secretion. Free fatty acids are transported across the brush border membrane (BBM)—mainly by passive
diffusion and to a lesser extent by fatty acid transporters (CD36, FATP4, and FABPpm)—and then to the endoplasmic reticulum (ER)
by intracellular fatty acyl CoA transporters I-FABP (FABP-2) and L-FABP (FABP-1), where free fatty acid is resynthesized into
triacylglycerol as described in Figure 1. Dietary cholesterol is transported across the BBM by the cholesterol transporters Niemann-
Pick C1-like 1 (NPC1L1) and SR-B1. Free cholesterol can either be exported back to the lumen by ABCG5/8 or converted to
cholesteryl ester (CE) and transported to the ER by ACAT2. In the ER, newly synthesized ApoB-48 is lipidated with triglyceride (TG),
CE, and phospholipid by microsomal triglyceride transfer protein (MTP) to form a primordial chylomicron (CMpri ). Further addition
of TG and cholesterol by MTP to the core of the primordial chylomicron generates a prechylomicron (CMpre ), which also acquires
apoA IV. The prechylomicron is exported in a prechylomicron transport vesicle (PCTV) by budding from the ER aided by L-FABP.
The PCTV fuses with the cis-Golgi aided by secretion-associated, Ras-related GTPase 1B (Sar1b) and soluble N-ethyl maleimide
sensitive-factor attachment protein receptor (SNARE) proteins. In the Golgi, the prechylomicron acquires ApoA1. Mature
chylomicrons are exported from the Golgi in vesicles and released into the basolateral surface of the enterocyte into the lymphatic
circulation. Cholesterol can also be secreted into the basolateral membrane (BLM), independent of ApoB-48, along with ApoA1 as a
high-density lipoprotein particle by the transporter ABCA1. Abbreviations: ABCA1, ATP–binding cassette transporter A1; ABCG5/8,
ATP-binding cassette transporter G5/G8; ACAT2, acyl CoA:cholesterol acyltransferase enzyme 2; CD36, cluster determinant 36;
FABPpm, fatty acid–binding protein plasma membrane; FATP4, fatty acid–transport protein 4; HDL, high-density lipoprotein;
I-FABP, intestinal fatty acid–binding protein; L-FABP, liver fatty acid–binding protein; VAMP7, vesicle-associated membrane
protein 7. Figure adapted with permission from Pan & Hussain 2012. Biochim. Biophys. Acta 1821:727–35 (116).
B-48 (ApoB-48) lipoprotein under the influence of microsomal triglyceride transfer protein
(MTP) in vitro and in vivo (73) (see Section 2.4 and Figure 2) and eventually secreted as part of
a chylomicron. Free cholesterol can also be secreted along with ApoA1 as a nascent high-density
ApoB-48:
apolipoprotein B-48 lipoprotein (HDL) particle under the influence of the ATP-binding cassette transporter G5/G8
(ABCA1) (16, 116) in vivo (Figure 2). In addition to secreting cholesterol into the circulation,
MTP: microsomal
triglyceride transfer the enterocyte can export cholesterol back into the lumen through two ATP-binding cassette
protein transporters that are thought to function as heterodimers: ABCG5 and ABCG8 (60) (Figure 2).
ABCA1: These two transporters are also important in ensuring that plant sterols are not absorbed.
ATP-binding cassette Loss-of-function mutations in either transporter in humans leads to sitosterolemia, characterized
transporter G5/G8 by an accumulation of plant sterols, tendon xanthomas in the presence of normal low-density
ABCG5/8: lipoprotein (LDL) cholesterol, and premature coronary artery disease (60).
ATP-binding cassette
transporter A1
2.3. Triglyceride Synthesis
MGAT:
monoacylglycerol Fatty acid entering the enterocyte is catalyzed by FATP4, which has acyl CoA synthetase activity,
acyltransferase to fatty acyl CoA (99, 146) in vitro. In the ER of the enterocyte, dietary MAG and fatty acid CoA
DGAT: are covalently bonded to form DAG (Figure 1). This reaction is catalyzed by monoacylglycerol
diacylglycerol acyltransferase (MGAT) enzymes (91, 177) in vitro. MGAT2 is expressed in the small intestine
acyltransferase of rodents and humans, whereas MGAT3 is expressed in the small intestine of humans only (23,
91). MGAT2 knockout mice have attenuated postprandial hypertriglyceridemia and resistance to
diet-induced obesity (176).
DAG is then further acylated by diacylglycerol acyltransferase (DGAT) enzymes (Figure 1).
This is achieved by the enzymes DGAT1 and DGAT2 in rodents, whereas human small intestine
expresses DGAT1 only (17, 21, 54, 148). Haas et al. (54) reported a family in which two siblings had
a homozygous mutation in DGAT1, with near undetectable DGAT1 expression. These individuals
presented with severe neonatal onset diarrhea, with one sibling passing away at the age of 17 months
but with improvement in symptoms with time in the other sibling. DGAT1 inhibitors are currently
being assessed for the treatment of hypertriglyceridemia, but their clinical development has been
hampered by the side effect of diarrhea (33). The phenotype of DGAT1 deficiency in humans is
more severe than that of DGAT1 knockout mice (which have normal but delayed fat absorption
and resistance to diet-induced obesity), possibly due to the presence of DGAT2 in mice (17).
MGAT3, expressed in the small intestine in humans, has DGAT activity in vitro (19, 91). It is
estimated that approximately 75% of intestinal TG synthesis is carried out by the esterification of
dietary MAG, with the majority being directed to chylomicron formation (116, 175) in vivo in rats.
Enterocytes can also synthesize TG from glucose via the glycerophosphate pathway (Figure 1),
although this is a relatively minor pathway in humans, accounting for less than 30% of enterocyte
TG synthesis. This TG is primarily stored in the cytosol of enterocytes (116, 175).
2.4. Chylomicron Synthesis

ApoB-48 is the major, nonexchangeable apolipoprotein of chylomicrons. It is encoded by the
APOB gene. Unlike the liver, which secretes the full-length ApoB-100 (4,536 amino acids), in the
intestine ApoB is post-transcriptionally edited by Apobec-1, resulting in the insertion of a prema-
ture stop codon and generation of a truncated ApoB protein that is 48% of the length of ApoB-100
(ApoB-48; 2,152 amino acids) (5). In vitro studies have shown that in the absence of lipidation,
ApoB-48 is degraded (100, 116). The enzyme MTP catalyzes the lipidation of ApoB-48 in the inner
leaflet of the ER (Figure 2). It is a heterodimer of a 97-kDa catalytic subunit and protein disulfide
isomerase. It catalyzes the addition of TG, cholesterol ester, and phospholipid to ApoB-48 to gen-
erate secretion-competent primordial chylomicrons in vitro. Unlike unlipidated ApoB-48, these
6.6 Dash et al.
primordial chylomicron particles can be stored in the apical aspect of the enterocytes, possibly in
the ER (100, 116). In the fasted state, the enterocyte secretes relatively lipid-poor chylomicron
particles (59). Under postprandial conditions, the primordial chylomicron particles are further
VAMP7:
lipidated with TG and cholesteryl ester to generate larger prechylomicron particles, which are vesicle-associated
transferred to the Golgi for maturation and secretion (91) (Figure 2). In addition to ApoB-48, membrane protein 7
chylomicrons have a number of exchangeable apolipoproteins. Apolipoprotein A-IV (ApoA-IV) is
an exchangeable lipoprotein that is incorporated into chylomicrons at an early stage within the ER.
It resides on the surface of chylomicrons and may be important for chylomicron synthesis and se-
cretion. ApoA-IV overexpression in vitro increases TG packaging of chylomicrons in the ER with
increases in MTP expression, although ApoA-IV overexpression in vivo is not associated with in-
creased fat absorption or chylomicron production (1). ApoA-IV knockout mice have reduced MTP
expression (117) but have no malabsorption of lipid or reduced chylomicron production (163).
Prechylomicron particles synthesized in the ER are transported to the Golgi for further matu-
ration. In vitro studies have shown that these relatively large particles are transported in PCTVs,
which comprise COPII proteins, ApoB-48, CD36, and FABP-1 as well as vesicle-associated mem-
brane protein 7 (VAMP7) (91, 141, 142) (Figure 2). FABP-1 is sufficient to initiate synthesis of
PCTV and its budding from the ER. FABP-1 is part of a cytosolic protein complex (comprising
Sar1b, Sec13, and small valosin-containing protein/p97-interactive protein) that prevents FABP-1
binding to the ER. Protein kinase C-zeta mediates phosphorylation of the Sar1b, in an ATP-
dependent manner, which disassembles the complex that permits binding of FABP-1 to the ER
and generation and budding of the PCTV in vitro (139). The PCTV then fuses with the cis-Golgi
by the interaction of VAMP7 with Golgi membrane proteins syntaxin 5, rbet1, and vit1a (91, 116,
141, 142). In the Golgi, the prechylomicron gains apoA-1, and ApoB-48 undergoes glycosylation.
Chylomicrons are then transferred from the trans-Golgi to the basolateral membrane via vesicles,
which exocytose the chylomicrons into the lamina propria and eventually into the circulation via
the lymphatic system (116) (Figure 2).
2.5. Chylomicron Clearance from the Circulation

Once in the circulation, chylomicrons acquire further exchangeable apolipoproteins such as apoC2,
apoC3, and apoE (26, 173). The TG component of the chylomicron is hydrolyzed by lipoprotein
lipase (LPL) expressed on the surface of endothelial cells of the vasculature of adipose tissue,
skeletal muscle, and myocardium. ApoC2 is a cofactor promoting LPL activity, whereas ApoC3
inhibits it (173). Loss-of-function mutations in LPL and ApoC2 in humans cause familial chy-
lomicronemia with marked hypertriglyceridemia and increased risk of acute pancreatitis (15, 61).
Conversely, loss-of-function mutations in apoC3 are associated with low plasma concentration of
TGs and remnant particles and protection from atherosclerotic cardiovascular diseases (27, 79).
Genetic mutations in humans have also revealed the physiological importance of lipase matura-
tion factor 1 (encoded by LMF1), glycophosphatidylinositol HDL-binding protein-1 (encoded
by GPHIB1), and ApoA5 (encoded by APOA5) in regulating chylomicron clearance (61). Lipase
maturation factor 1 is an ER protein that posttranslationally activates LPL. Glycophosphatidyli-
nositol HDL-binding protein-1 transfers LPL across and tethers it to the endothelial surface,
whereas ApoA5 interacts with LPL to promote chylomicron hydrolysis (77). Hydrolysis of chy-
lomicron TGs by LPL yields remnant particles that are potentially atherogenic (11, 89). These
remnant particles are removed from the circulation by the liver. ApoE facilitates the binding of
these remnants to the heparan sulphate proteoglycans on the surface of hepatocytes, which are
then internalized by the action of the LDL receptor and LDL receptor-related protein 1 (69,
167). It is worth noting that TG-rich very-low-density lipoprotein (VLDL) particles produced
Diet
Genetic variants Circulation factors

and disorders
Drugs and
Circadian regulation Chylomicron bariatric surgery
secretion
? Microbiota ? Neural regulation
Metabolic
disorders
Figure 3
Summary of known and potential novel factors regulating chylomicron secretion. Question marks denote
factors that potentially regulate chylomicron production and warrant further investigation.
by the liver are also removed by similar saturable mechanisms, with competition between VLDL
and chylomicrons for removal.
In summary, dietary lipid is digested, absorbed, incorporated into chylomicrons, and trans-
ported in the circulation before being cleared. This process involves a complex interaction between
dietary lipid, transporters, lipoproteins, and enzymes.
3. REGULATION OF CHYLOMICRON PRODUCTION

Although ingested fat is the major driver of chylomicron production, recent research has shown
that chylomicron production is a highly regulated process and that other factors affect this pro-
cess, including nonlipid nutritional factors, hormones and circulating factors, genetic variants,
circadian rhythms, nutraceuticals, and therapeutic interventions (pharmacological agents as well
as bariatric surgery) (61, 70, 114, 174) (Figure 3). These findings are important, as increased
chylomicron production contributes to postprandial hypertriglyceridemia, an independent risk
factor for atherosclerosis (8, 111, 174). In the postprandial state, there is a small increase in the
number of chylomicron particles, but each particle is considerably larger, with increased lipid
content (59). Following lipolysis, as described above (Section 2.5), these chylomicrons are con-
verted to chylomicron remnant particles. In certain conditions such as insulin resistance and type
2 diabetes, circulating chylomicron and remnant particles increase; the latter are thought to be
atherogenic (173). Reducing chylomicron production may therefore be a potential therapeutic
target in reducing atherosclerotic risk in certain patient populations. In this section, we discuss
some of the factors regulating chylomicron production. For many of the factors reported, kinetic
studies assessing the production and clearance of chylomicrons have not been reported, and there-
fore studies assessing the impact of these factors on chylomicron or plasma TG concentrations
are included in the following discussion.
3.1. Nutritional Factors

3.1.1. Lipids.
Acute studies of the effects of lipids. In addition to the quantity of dietary lipid, the com-
position of ingested fat affects chylomicron concentration. Low doses of dietary fat (<15 grams)
6.8 Dash et al.
have been shown not to increase chylomicron concentration acutely. With moderate doses of fat
(30–50 gram), a dose-dependent increase in plasma TG and chylomicron concentration is seen
(39). Higher doses of fat consumption elicited a greater TG response, but it was no longer dose
dependent (84, 102).
Studies assessing the effects of acute ingestion of meals enriched with saturated, monounsatu-
rated, and polyunsaturated fatty acids have yielded conflicting reports with regard to postprandial
TG, ApoB-48, and/or chylomicron concentration. Lower TG concentration in the chylomicron
fraction was seen following ingestion of a polyunsaturated fatty acid–enriched meal compared to
a meal with saturated fatty acid (74). The monunsaturated fatty acid–enriched meal elicited an
intermediate response (74). A similar finding was seen by Weintraub and colleagues (164), who
reported lower chylomicron concentration after ingestion of n-3 and n-6 polyunsaturated fatty
acid–enriched meals compared to meals enriched with saturated fatty acid. However, these findings
have not been replicated in other studies, which have reported a lower chylomicron concentration
with saturated fatty acid (97) or no difference between saturated and monounsaturated fatty acids
(131). One potential explanation is that the fatty acid composition of habitual chronic food in-
take can affect the postprandial response (164). These studies did not formally assess chylomicron
production rates.
Chronic studies of the effects of lipids. Short-term consumption of isocaloric diets rich in
saturated fatty acid, n-6 fatty acid, and n-3 fatty acid over 25 days in healthy normolipidemic
individuals resulted in greater chylomicron concentration with saturated fatty acid compared to
n-3 fatty acid; concentration was intermediate with n-6 FA. The production rate of chylomicrons
was not assessed, but chylomicrons from individuals on the n-3 and n-6 fatty acid diets were
more susceptible to lipolysis in vitro (164), suggesting that increased clearance contributes to the
increased chylomicron concentration. More recently, Wong et al. (168) demonstrated that in obese
individuals on a hypocaloric diet, 12-week supplementation with n-3 fatty acid ethyl ester (46%
eicosapentaenoic acid and 38% docosahexaenoic acid) reduced fasting and postprandial ApoB-48
and TG concentrations. Kinetic studies revealed increased fractional catabolic rates with decreased
production in the fasted state but not in the postprandial period (168).
3.1.2. Carbohydrates. Epidemiological studies have reported an association between plasma

TG and consumption of refined carbohydrates and monosaccharides such as fructose (14). Very
few studies have assessed chylomicron concentration and secretion in response to short-term
interventions with increased dietary carbohydrate. Parks et al. (119) compared the effect of a five-
week high-fat, low-carbohydrate diet to treatment with a low-fat, high-carbohydrate diet. Both
diets were isocaloric, and the proportion of calories from simple monosaccharides and complex
carbohydrates was similar. Plasma TG and fasting ApoB-48 concentration increased with the low-
fat, high-carbohydrate diet, but chylomicron production rates were not formally assessed (119).
A potential confounder in assessing the long-term effects of nonisocaloric, high-carbohydrate
diets is weight gain with worsening insulin resistance, which can exacerbate postprandial chy-
lomicron and TG responses. This can be avoided with acute studies. However, acute studies of
the effect of addition of carbohydrates to test meals have not always revealed concordant results,
with both increased (24, 51, 57, 76) and decreased (166) responses reported. This may be due to
differences in the type of carbohydrate (complex versus simple sugars), the glycemic index (57),
and the ensuing insulin response [insulin is known to suppress chylomicron production (120)] as
well as the varying rates of gastric emptying in response to the type of meal (166), all of which
can affect chylomicron production. In a recent study, we aimed to circumvent these issues as well
as the potentially indirect effects of carbohydrate-induced weight gain and insulin resistance in
chronic studies (171). We studied the acute effects of intraduodenal infusion (to negate any ef-
fects of gastric emptying) of the enteral monosaccharides glucose and fructose on chylomicron
production in a constant fed state using stable isotope infusion and steady state mathematical
TRL:
triglyceride-rich modeling. To prevent any fluctuations in pancreatic hormone production (principally insulin)
lipoprotein that can affect chylomicron production, a pancreatic clamp was deployed in which somatostatin
FFA: free fatty acid was infused to inhibit endogenous pancreatic hormone production, along with replacement doses
of insulin, glucagon, and growth hormone (171). In this experimental setting, we were able to
demonstrate that both glucose and fructose directly increased triglyceride-rich lipoprotein (TRL)
ApoB-48/chylomicron production in lean, healthy men compared to placebo. Interestingly, both
treatments modestly increased plasma glucose levels (171). It remains to be seen whether increased
plasma glucose per se can enhance chylomicron production. The mechanism of increased chy-
lomicron production with enteral glucose and fructose in humans is not clear. In P. Obesus and
Caco-2/15 cells, high glucose concentration lowered adenosine monophosphate-activated pro-
tein kinase (AMPK) levels with reduced phosphorylation of acetyl-CoA carboxylase and increased
lipogenesis in enterocytes (58). A similar mechanism could potentially contribute to the increase
in chylomicron production seen with glucose and fructose (secondary to a rise in plasma glucose)
in humans. In rodents, glucose is known to increase lipogenesis in hepatocytes by activating car-
bohydrate response element-binding protein (ChREBP) (48). Fructose can also activate hepatic
ChREBP as well as SREBP1c in rodents to stimulate lipogenesis (83). ChREBP and SREBP1c
are also expressed in the enterocyte and potentially could be activated by glucose and fructose
(71, 124).
3.1.3. Protein. Very few studies have assessed changes in chylomicron concentration in response
to dietary protein intake. Mamo et al. (90) compared the effects of six weeks’ consumption of two
isocaloric diets in mildly hypertriglyceridemic men; one diet was high in protein in the form of
lean red meat, and the other had lower protein content. Following a fat challenge, participants
on the high-protein diet had an attenuated increase in ApoB-48 concentration (∼85% less than
the increase in subjects on the low-protein diet). There was no difference in insulin sensitivity or
weight between the groups (90). Notably, the low-protein group had a higher carbohydrate intake,
and therefore whether the effect on chylomicron concentration was causally linked to differing
protein intake alone is not known.
Protein consumption can acutely affect the postprandial TG response. In healthy individuals the
consumption of casein along with a fat meal attenuates the postprandial TG response (165). This
is likely mediated by the increased insulin response with consequent reduction in plasma free fatty
acid (FFA). Chylomicron concentration and production were not formally assessed, but increased
insulin and reduced FFA are known to suppress chylomicron production (42, 120). The type of
protein may also impact the acute postprandial TG response to a high-fat meal. In individuals with
type 2 diabetes, consumption of 45 grams of whey protein in a test meal comprising 100 grams
of butter and 45 grams of carbohydrate was associated with reduced plasma TG compared to
when the whey protein was substituted with the same amount of casein, cod, or gluten (101). The
whey test meal was associated with lowered plasma FFA and glucose, both of which are known to
stimulate chylomicron production (40, 171).
3.1.4. Dietary fiber. Addition of dietary wheat fiber has been shown to attenuate the chylomicron
TG response to a mixed meal (20). However, total serum ApoB (ApoB-100 and ApoB-48) did not
differ significantly between the groups.
In summary, alterations to dietary macronutrients have been shown to modulate postprandial
plasma TG and in some cases chylomicron concentration. Enteral monosaccharides have been
6.10 Dash et al.
shown to convincingly increase chylomicron production rates. Very few studies, however, have
assessed chylomicron production rates in response to other dietary alterations, and therefore
confirmatory studies are warranted to assess whether these factors affect chylomicron production.
3.2. Hormonal, Local, and Circulating Factors

3.2.1. Insulin. It is well established that insulin acutely lowers plasma TG concentration, in part
by suppressing production of VLDL particles by the liver (88). We have also demonstrated that
raising plasma insulin concentration by means of a hyperinsulinemic, euglycemic clamp acutely
suppresses ApoB-48-containing chylomicron production by the intestine, in response to con-
stant feeding, in healthy humans (120). The hyperinsulinemia was associated with a reduction in
circulating FFA. If the decline in FFA was prevented with coinfusion of intralipid (a synthetic
TG emulsion) and heparin (which releases LPL from the endothelial surface, thus stimulating
intravascular lipolysis and increasing circulating FFA concentration by ∼2- to 3-fold), the sup-
pressive effects of insulin on chylomicron production were partially abrogated, suggesting that
insulin reduces chylomicron production in part by suppressing FFA (120) and in part by a non-
FFA-mediated, possibly direct, effect. Similar effects were seen on ApoB-100-containing VLDL
particles. Insulin has been shown to suppress ApoB mRNA translation, in vitro in HepG2 cells,
via the 5 UTR. This effect is dependent on both PI3 kinase and mTOR signaling (143). In mice,
the transcription factor FoxO1 increases MTP expression and VLDL secretion. Insulin-mediated
nuclear exclusion of FoxO1 abrogates this effect (81). Whether insulin suppresses ApoB-48 mRNA
translation via a similar signaling pathway has not been established.
3.2.2. Free fatty acid. As alluded to above, FFA can increase TRL production by both the
liver and gut, and insulin suppresses its production in part by suppressing FFA concentration.
We have demonstrated this under controlled experimental conditions (40). Under conditions of
constant feeding, intravenous intralipid and heparin infusion increases chylomicron production
by 69% compared to placebo as judged by steady state mathematical modeling with stable isotope
infusion (40). Similar findings have been observed in Syrian golden hamsters in vivo and ex vivo
in primary cultures of enterocytes (87). Further, oleic acid but not glycerol increased chylomicron
production rate (87). This finding is of particular relevance because increased FFA flux is seen in
insulin resistance and type 2 diabetes and may play a role in the chylomicron overproduction of
these conditions. Previous tracer studies in pancreatectomized dogs have suggested that circulating
nondietary FFA is taken up by enterocytes, esterified, and released as chylomicrons (147).
3.2.3. Glucagon-like peptide-1. Glucagon-like peptide 1 (GLP-1) is encoded by the

proglucagon gene and secreted by enteroendocrine L cells of the distal gut in response to nutrient
ingestion. It has a number of metabolic effects including but not limited to an increase in glucose-
stimulated insulin secretion, and reductions in gastric emptying, glucagon secretion, and appetite
(6). GLP-1 analogues and dipeptidyl peptidase IV (DPPIV, which degrade endogenous GLP-1
along with a number of other peptides) inhibitors are approved treatments for type 2 diabetes (37).
Pharmacological manipulation of the GLP-1 receptor by administration of exendein-4, a GLP-1
analogue, or a DPPIV inhibitor attenuates postprandial hypertriglyceridemia and chylomicron
secretion in Syrian golden hamsters in vivo, and exendin-4 reduced chylomicron secretion from
primary hamster enterocytes (67). Further, chylomicron secretion is attenuated in GLP-1 receptor
knockout mice and in mice treated with a GLP-1 receptor antagonist exendin [9-39], which sug-
gests that endogenous GLP-1 plays a role in modulating chylomicron production (67). Treatment
with the GLP-1 analogue exenatide for one year in patients with diabetes lowered postprandial TG
and ApoB-48 concentration compared to patients treated with the long-acting insulin analogue
glargine, despite similar glycemic control (18). Similar effects have been seen with the administra-
tion of other GLP-1 analogues or DPPIV inhibitors (93, 154, 170). Acute infusion of native GLP-1
GLP-1: glucagon-like
peptide-1 in healthy volunteers attenuated the postprandial response to a test meal (95). In individuals with
impaired glucose tolerance or newly diagnosed type 2 diabetes, treatment with a single dose of
exenatide attenuated the postprandial TG and ApoB-48 increment following a mixed meal (136).
These long-term and acute studies with GLP-1/GLP-1 analogues and DPPIV inhibitors did not
assess chylomicron production rates. Further, potential extraintestinal actions could indirectly
affect chylomicron secretion, and thus these effects may not be direct effects of GLP-1/GLP-1
analogues. In long-term studies with exenatide, weight loss (37) with ensuing improvement in
insulin sensitivity is a potential and likely contributor to the reduced postprandial TG concen-
tration. In acute studies, delayed gastric emptying (with GLP-1 analogues) and increased insulin
secretion (with both GLP-1 analogues and DPPIV inhibitors) (37) are likely contributors to the
diminished ApoB-48 and TG response to a meal stimulus. Improved glycemic control in patients
with type 2 diabetes/impaired glucose tolerance is a further confounder in long-term studies. In
order to examine the direct effects of GLP-1 on chylomicron production, in the absence of the
aforementioned confounders, we studied the acute effects of a single dose of exenatide in lean,
healthy normoglycemic men (169). To circumvent the effects of exenatide on gastric emptying,
we utilized a constant infusion of a liquid meal through a nasoduodenal tube during the course of
the study. We deployed a pancreatic clamp to prevent major fluctuations in pancreatic hormone
concentration as described above. Under these experimental conditions, exenatide acutely reduced
the TRL ApoB-48 production rate by 38%. In a follow-up study we demonstrated that sitagliptin,
a DPPIV inhibitor, similarly acutely reduced chylomicron production by ∼50% in healthy men
(172). A recent study has also demonstrated an ∼16% reduction in chylomicron production in
patients with type 2 diabetes treated with sitagliptin for six weeks (155).
3.2.4. Glucagon-like peptide-2. As is the case with GLP-1, GLP-2 is encoded for by the
proglucagon gene, is secreted by intestinal L cells in response to nutrient ingestion, and is
degraded by DPPIV (38). It has various effects on the gastrointestinal tract including reducing
gastric emptying, promoting nutrient absorption, reducing inflammation, promoting adaptive
bowel growth, and reducing apoptosis. These properties of GLP-2 are beneficial in the treatment
of malabsorption in short bowel syndrome. The degradation-resistant GLP-2 analogue teduglu-
tide is now an approved treatment for short bowel syndrome (38). In the Syrian golden hamster,
GLP-2 treatment increases lipid absorption, likely via increased glycosylation of the fatty acid
transporter CD36. It also increases chylomicron secretion (68). In humans, intravenous GLP-2
infusion increases postprandial plasma TG concentration in response to a test meal (96). To
assess whether GLP-2 increases plasma TG by increasing chylomicron production, we assessed
the acute effect of GLP-2 on chylomicron production in lean healthy men (30). Participants were
studied under conditions of constant intraduodenal feeding (as GLP-2 reduces gastric emptying)
and a pancreatic clamp (as nutrient infusion and GLP-2 can affect pancreatic hormone secretion)
with stable isotope enrichment methodology as described above. Subcutaneous injection of
GLP-2 transiently increased TRL ApoB-48 concentration for one to three hours following
administration; however, in contrast to other regulators of chylomicron production, mathematical
modeling suggested that this was not due to increased de novo synthesis of ApoB-48 but rather due
to the release of nonisotopically enriched, preformed ApoB-48-containing chylomicrons (30). As
the gut can store lipid from a previous meal as well as preformed ApoB-48, which can subsequently
be mobilized, we evaluated whether GLP-2 releases chylomicrons containing stored enteral lipid
and previously synthesized ApoB-48. Participants were given a liquid meal enriched with retinyl
6.12 Dash et al.
palmitate in order to label chylomicrons synthesized from the meal and were not permitted any
further food intake until the conclusion of the study. Subcutaneous GLP-2 administration seven
hours later robustly increased TRL TG, TRL ApoB-48, TRL retinyl palmitate, and chylomicron
retinyl palmitate. These studies indicate that GLP-2 increases chylomicron concentration by
releasing stored enteral lipids and presynthesized ApoB-48 as chylomicrons (30). The exact
mechanism by which GLP-2 releases chylomicrons is currently unknown and warrants further
investigation. The effects of GLP-2 are likely indirect, as the GLP-2 receptor is not expressed
on enterocytes but is expressed in subepithelial myofibroblasts, enteric neurones, and enteroen-
docrine cells (38). GLP-2 is known to increase mesenteric blood flow by upregulating endothelial
nitric oxide synthase and increasing nitric oxide activity (38, 53). The resulting increase in intersti-
tial hydration could potentially release stored, preformed chylomicrons from the lamina propria
and lymphatics (156). GLP-2 is not known to affect hydrolysis of stored enteral lipids, a requisite
step for mobilization of stored lipid before reesterification and conjugation to ApoB-48 in the
ER and Golgi. It is worth noting that in this study a pharmacological dose of GLP-2 was utilized
(30). The contribution of endogenous GLP-2 to chylomicron secretion is currently unknown.
The above studies with GLP-1 and GLP-2 raise further questions. Both hormones are secreted
in equimolar amounts by L cells but have opposing effects on chylomicron secretion (63). In normal
physiological, postprandial conditions when both hormones are secreted, which hormone, if any,
has the dominant effect? In Syrian golden hamsters, coinfusion of equimolar amounts of GLP-1
and GLP-2 following oral gavage resulted in a predominant GLP-2 effect in that chylomicron
secretion increased (63). This may be due to the more rapid degradation of GLP-1 by DPPIV.
Consistent with this, a more prolonged coinfusion of GLP-1 and GLP-2 or administration of a
DPPIV inhibitor attenuated postprandial chylomicron secretion. Interestingly, hamsters rendered
insulin resistant by high-fructose feeding were more sensitive to GLP-2 and less sensitive to GLP-
1 in terms of chylomicron secretion (63). These findings await confirmation in humans, although
as discussed above DPPIV inhibitors reduce chylomicron production in humans (155, 172).
In addition to GLP-1 and GLP-2, DPPIV inhibitors prevent degradation of glucose-dependent
insulinotropic polypeptide (GIP), which is important for its glucose-lowering effects (6). GIP
administration in dogs reduces chylomicron concentration by increasing its clearance (162). In
humans, GIP administration in fasted, obese, normoglycemic men reduced FFA concentration,
a known stimulus for chylomicron production, by inhibiting adipose tissue lipolysis but with no
significant change in fasting plasma TG (50). It remains to be established whether GIP reduces
postprandial chylomicron production.
In summary, circulating factors such as fatty acids and GLP-2 increase chylomicron production,
whereas insulin, GLP-1, and potentially GIP reduce chylomicron production.
3.3. Pharmacological Agents, Nutraceuticals, and Other Treatments

Several pharmacological agents and nutraceuticals have been shown to attenuate the postprandial
TG response and chylomicron concentration.
3.3.1. Statins. These commonly prescribed cholesterol-lowering agents inhibit cholesterol syn-
thesis by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol
biosynthesis. Statins are known to effectively reduce LDL cholesterol concentration and to a
lesser extent plasma TG. Kinetic studies in patients with type 2 diabetes and hypertriglyceridemia
have demonstrated that statins reduce production and enhance clearance of TRL ApoB-48 with
a net reduction in TRL ApoB-48 pool size (64).
3.3.2. Fibrates. These drugs are known to lower fasting and postprandial plasma TG concen-
trations, presumably by targeting the nuclear receptor peroxisome proliferator-activated receptor
(PPAR)α. Studies in CD36 knockout mice have demonstrated that fenofibrate reduces postpran-
dial chylomicron concentration with reduced intestinal ApoB-48 mRNA expression and reduced
ApoB-48 and TG concentration in intestinal lymph, suggesting reduced production (133). In
humans with type 2 diabetes, fenofibrate reduced TRL ApoB-48 pool size predominantly by in-
creasing its clearance, with no significant change in production (64). Fenofibrate has been shown
to lower apoC3 concentration, which would be expected to increase chylomicron clearance (86).
3.3.3. Ezetimibe. Ezetimibe is a drug commonly used to lower LDL cholesterol, often as an
adjunct to statins. It blocks the Niemann-Pick C1-like 1 receptor to reduce cholesterol absorption
and increases expression of the LDL receptor (127). In addition, it reduces the expression of
lipid transporters SR-BI and ABCA1 in vitro in intestinal Caco-2 cells (43). In humans with type
2 diabetes, ezetimibe treatment in combination with a statin for six weeks reduces postprandial
chylomicron concentration compared to statin treatment alone (12). In Syrian golden hamsters
fed a high-fructose and high-fat diet, ezetimibe reduced TRL ApoB-48 production (104). This
was associated with an improvement in insulin sensitivity and reduced expression of jejunal mRNA
expression of ApoB-48 and several lipogenic and fatty acid transporter genes including Srebp-1c,
Sr-b1, Ppar-γ , and Abcg1 and protein expression of the fatty acid transport protein FATP4 and
SR-B1(104).
3.3.4. Insulin sensitizers. Because insulin resistance and type 2 diabetes are linked with increased
production of chylomicrons, one would expect treatment with insulin sensitizers to reduce chy-
lomicron production. In overweight/obese humans with type 2 diabetes, treatment with metformin
improved insulin sensitivity with no improvement in postprandial lipid profiles. In obese individu-
als with impaired glucose tolerance, however, postprandial chylomicron concentration improved
with metformin treatment (52). In the diabetic rat Psammomys obesus, metformin treatment acti-
vated intestinal AMPK with phosphorylation of acetyl-CoA carboxylase and elevation in carnitine
palmitoyltransferase-1, which was associated with a reduction in diabetic dyslipidemia (58). In
overweight/obese humans with type 2 diabetes, treatment with rosiglitazone improved insulin
sensitivity with no improvement in postprandial lipid profiles. In fact, postprandial ApoB-48 con-
centration was higher with rosiglitazone (75). In nondiabetic men, treatment with rosiglitazone
also increased TRL ApoB-48 concentration during constant feeding due to an increase in TRL
ApoB-48 production to clearance ratio. This effect was seen despite an improvement in insulin
sensitivity (41).
3.3.5. MTP inhibitors. MTP is a critical enzyme for the lipidation of ApoB in the liver and
intestine. In recent years, lomitapide, a small molecule inhibitor of MTP, has been evaluated as a
treatment for homozygous familial hypercholesterolemia (125). It substantially lowers both LDL
cholesterol and TG with reduced ApoB production (28, 29). Consistent with the phenotype of
patients with loss-of-function mutations in MTP, it is associated with hepatic steatosis and de-
ranged liver function tests. Although it frequently causes diarrhea and steatorrhea, malabsorption
of fat-soluble vitamins A and D does not seem to occur, although there was a reduction in vitamin
E (28, 29). Intestinal-specific inhibitors of MTP are currently in development (98).
3.3.6. DGAT1 inhibitors. DGAT1 catalyzes the final step in TG synthesis and regulates
chylomicron secretion. Its inhibition has been postulated as a potential therapy for obesity and
type 2 diabetes. The selective DGAT1 inhibitor AZD7687 has recently been shown to attenuate
6.14 Dash et al.
postprandial hypertriglyceridemia. However, nausea, vomiting, and diarrhea were seen in a

dose-dependent manner (33). This is consistent with the phenotype of intractable diarrhea seen
in humans with DGAT1 mutations (54). The long-term efficacy and tolerability of this drug
remain to be established.
3.3.7. Resveratrol. This polyphenol is present in red wine and available as an over-the-counter
nutraceutical supplement. It activates the NAD+ -dependent deacetylase sirtuin 1, which is thought
to mediate the beneficial effects of caloric restriction in rodent models. In mice, treatment with
resveratrol improves insulin sensitivity and hepatic steatosis in diet-induced obesity (9, 137). Some
(13, 151) but not (122) all human studies have shown improvements in insulin sensitivity and plasma
TG with resveratrol. We investigated the effects of two weeks’ administration of high doses of
resveratrol (1,000 mg daily for week one then 2,000 mg daily for week two) to obese, mildly
hypertriglyceridemic men (32). TRL ApoB-48 production was assessed in a constant fed state
with primed constant infusion of D3-leucine. We found that resveratrol reduced TRL ApoB-
48 production, with a possible trend toward reduced clearance such that overall there was a
trend toward reduced TRL ApoB-48 concentration (32). These effects were seen in the absence
of significant changes in insulin sensitivity as judged by homeostatic model assessment–insulin
resistance (HOMA-IR). Because the sample size was small and the treatment duration was short,
it is not clear whether the reduced chylomicron production with resveratrol will translate into
reduced TRL ApoB-48 concentration with longer treatment periods in larger cohorts (32). Long-
term treatment with a grapefruit extract containing 8 mg of resveratrol was associated with lower
fasting ApoB concentration (153).
3.3.8. Bariatric surgery. Obesity is associated with insulin resistance and dyslipidemia. Bariatric
surgery is a proven treatment for obesity and results in long-term weight loss and improved
metabolic parameters, including diabetes and its complications as well as dyslipidemia (72, 144).
In a recent study, nondiabetic obese patients undergoing bariatric surgery had lipoprotein ki-
netics assessed with stable isotope infusion in the constant fed state one month prior to and six
months after bariatric surgery (114). In patients undergoing sleeve gastrectomy (a restrictive pro-
cedure), TRL ApoB-100 and ApoB-48 concentrations declined, with reduced production rates of
TRL ApoB-100 and ApoB-48 and increased TRL ApoB-100 clearance. Gastric bypass surgery (a
restrictive and malabsorptive procedure) was associated with reduced TRL ApoB-100 concentra-
tion but no significant change in TRL ApoB-48 concentration (114). This study was limited by
small sample size, so definite differences between the two bariatric surgical procedures cannot be
conclusively established.
In summary, various treatment modalities reduce chylomicron concentration, in many cases by
reducing chylomicron production rate. Statins, ezetimibe, MTP inhibition, DGAT1 inhibition,
resveratrol, and bariatric surgery have been shown to reduce chylomicron concentration.
3.4. Circadian Regulation of Chylomicron Secretion

Circulating plasma TG concentration shows a diurnal variation, with concentration highest at
night (135). Further, short-term changes simulating shift work resulted in increased postprandial
glucose and insulin, which initially attenuated plasma TG but with a prolonged and delayed peak
resulting in higher postprandial TG concentration (56). Disruptions in circadian rhythms have
been proposed to contribute to dyslipidemia and insulin resistance (94).
Work from Hussain & Pan (70) has demonstrated that MTP, ApoB, ApoA-IV, and nocturnin
show diurnal variation, which in turn affects intestinal lipid absorption and chylomicron assembly
that can be modified by light exposure and food availability. The suprachiasmatic nucleus, the
master regulator of circadian rhythm, responds to light signals with increased expression of two
genes: Bmal1 (brain and muscle ARNT-like protein 1) and Clock (circadian locomotor output
Bmal1: brain and
muscle ARNT-like cycles kaput), which dimerize and interact with E-boxes in the promoter regions of two genes,
protein 1 period (Per) and cryptochrome (Cry). Per and Cry inhibit the expression of Clock and Bmal1 in
Clock: circadian an autoregulatory loop. Clock and Bmal1 heterodimers can also regulate the expression of other
locomotor output genes, including nuclear receptors such as RORα (RAR-related orphan receptor alpha) and Rev-
cycles kaput Erbα (70). Peripheral cells [outside of the central nervous system (CNS)] such as enterocytes also
express Clock and Bmal1 with diurnal variation. Clock mutant mice have increased lipid absorption
with increased MTP expression during the daytime, when expression is usually low (115). This
is due to abrogated Clock-mediated upregulation of small heterodimeric partner (SHP), which
usually suppresses MTP expression (118). Nocturnin is a clock-regulated deadenylase that regu-
lates mRNA expression by removal of its polyA tail (36). Nocturnin knockout mice are resistant
to diet-induced obesity and have increased cytoplasmic lipid droplet accumulation and reduced
chylomicron secretion. Reduced expression of Perilipin 2, Dgat2, ApoAIV, and Atgl was seen (36).
ApoAIV knockout mice have attenuated TG concentration at night with blunted response to
feeding during the day. This is thought to be due to reduced Mtp expression as a consequence
of reduced expression of the transcription factors forkhead box protein (FOX)A2 and FOXO1,
which usually upregulate Mtp expression (117).
In summary, chylomicron production undergoes diurnal variation with changes in the gene
expression of key proteins including MTP, ApoAIV, ApoB, and nocturnin.
4. THE GUT AS A LIPID STORAGE ORGAN

Most of the regulators of chylomicron production described in this review thus far affect de
novo production of chylomicron particles. Although the gut is very efficient at absorbing and
rapidly incorporating dietary lipid into newly synthesized chylomicrons, it can also store a portion
of the absorbed dietary lipid, delaying its release in chylomicrons. This can be in the form of
neutral lipid within cytosolic lipid droplets of enterocytes or stored chylomicrons in the lamina
propria and lymphatics (130). These stored lipids can then be mobilized several hours later in
response to stimuli including mixed-meal ingestion (44), glucose (130), sham feeding (22), and—
as recently demonstrated—the gut hormone GLP-2 (30). Storage of dietary lipids in the gut has
been demonstrated indirectly by ingestion of a meal labeled with retinyl palmitate (30), or with
13
C triolein (22), or with a certain composition of fatty acid (47), with a subsequent rise followed
by a decline in the concentration of labeled chylomicrons. Ingestion of a second meal or sham
feeding is associated with an increase in labeled chylomicrons, suggesting that stored dietary lipids
from the initial meal were being mobilized (22, 47). Robertson and colleagues (130) convincingly
demonstrated the storage capacity of the gut by performing jejunal biopsies in patients undergoing
endoscopy. These patients had a lipid-rich meal prior to the procedure, and lipid deposits were
seen in the cytosol of the enterocyte as well as the lamina propria. In patients given glucose one
hour prior to the procedure, these lipid deposits were no longer seen, suggesting that the lipid
deposits can be mobilized by oral glucose. In parallel studies, glucose ingestion was associated
with a rise in circulating chylomicron concentration (130).
Adiposity and fat mass appear to be positively correlated and a major determinant of gut storage
(22). Whether other factors affect this process and subsequent mobilization remains to be explored.
In summary, the gut can store dietary lipid for several hours, and lipid can be mobilized and
secreted in chylomicrons by mixed-meal ingestion, glucose, sham feeding, and GLP-2. It is highly
likely that additional stimulants of intestinal lipid mobilization will be identified in the future.
6.16 Dash et al.
5. PLASMA CHYLOMICRON CONCENTRATION IN INSULIN

RESISTANCE AND TYPE 2 DIABETES AND ITS POTENTIAL
ROLE IN ATHEROSCLEROSIS
5.1. Chylomicrons in Insulin Resistance and Type 2 Diabetes

Increased chylomicron production and reduced clearance are features of insulin-resistant states
and type 2 diabetes and contribute to postprandial hypertriglyceridemia in these conditions (173).
Hamsters rendered insulin resistant by high-fructose feeding have increased production of chy-
lomicrons in both fasted and fed states (55). This is due to increased stability of ApoB-48, increased
MTP mass, and enhanced lipogenesis. These effects were recapitulated ex vivo and were not seen
with short-term fructose feeding (55). In this model of insulin resistance, acute hyperinsulinemia
fails to suppress TRL ApoB-48 production (as it does in insulin-sensitive cultured hepatocytes,
enterocytes, animal models, and humans) and is associated with reduced insulin receptor sub-
strate (IRS)-1 phosphorylation and protein expression of Akt and increased protein expression of
the p110 subunit of phosphoinositol 3 kinase, protein tyrosine phosphatase 1B, and basal levels
of extracellular signal–regulated kinase (ERK) (46). Modulating the ERK signaling pathway by
inhibition of mitogen-activated kinase/ERK1/2 significantly decreased ApoB-48 synthesis and se-
cretion (46). These effects may be explained in part by the increased FFA flux seen with insulin
resistance. Acute elevation of TGs and FFA in hamsters with intralipid and heparin increases
chylomicron production (87). These findings in Syrian golden hamsters have, for the most part,
been replicated in humans. In humans with a range of insulin sensitivity, hyperinsulinemia and
insulin resistance were associated with increased TRL ApoB-48 production (40). Similarly, acute
elevation in FFA with intralipid and heparin increased TRL ApoB-48 production (42). In patients
with type 2 diabetes, TRL ApoB-48 production is increased (65), and the acute suppressive effect
of insulin on TRL ApoB-48 production is absent (110). In obese patients undergoing bariatric
surgery, duodenal biopsies from insulin-resistant patients revealed reduced Akt phosphorylation
and enhanced MAPK phosphorylation and increased lipogenesis and ApoB-48 biogenesis ex vivo
compared to insulin-sensitive patients; these results were associated with increased expression of
inflammatory markers and oxidative stress (159). Further, as discussed in Section 3.3.8, treat-
ment of obese insulin-resistant nondiabetic patients with sleeve gastrectomy was associated with
a reduction in chylomicron concentration and production. This reduction was associated with a
significant decline in insulin sensitivity (114).
In summary, the enterocyte is an insulin-sensitive organ. Acute hyperinsulinemia suppresses
chylomicron secretion in insulin-sensitive, healthy animals and humans and ex vivo in cultured
enterocytes. Insulin resistance and type 2 diabetes are associated with increased chylomicron
production and resistance to the acute suppressive effect of insulin, which contribute to the post-
prandial hypertriglyceridemia associated with these conditions.
5.2. Chylomicrons and Atherosclerosis

Increased chylomicron concentration resulting from increased production and reduced clearance
contributes to the postprandial hypertriglyceridemia seen in conditions such as insulin resistance
and type 2 diabetes (173). Hypertriglyceridemia, particularly in the postprandial state, is a risk
factor for atherosclerotic disease (8, 111). TG-rich lipoproteins, including chylomicrons, yield
remnant particles and FFA following LPL-mediated lipolysis. These remnant particles, relatively
rich in cholesteryl ester, can increase macrophage foam cell formation, a key step in atherosclerosis
(11). In addition, remnant particles can alter endothelial function by promoting progenitor cell
senescence (89) and apoptosis (138) due to oxidative stress as well as enhance the inflammatory
response to TNF-α (152). FFA generated from TRL lipolysis can also induce endothelial
inflammation (161). Following perfusion of carotid arteries derived from Watanabe heritable
hyperlipidemic rats with chylomicron remnants, increased cholesterol was seen in the intima
due to retention of ApoB-48-containing lipoproteins (123). More recently, in two independent
studies, individuals with loss-of-function mutations in APOC3 and low plasma TGs have been
shown to have a lower risk of atherosclerotic disease (27, 79). Whether this is due to lower ApoC3
per se, reduced remnant concentration, or reduced LDL remains to be established (25). Similarly,
genetic variants in APOA5 that are associated with elevated and low plasma TG are associated
with increased and decreased risk of myocardial infarction, respectively. Although this suggests a
causal relationship, it has not been established whether these variants alter other lipoproteins (80).
Recently, Mendelian randomization studies have also demonstrated that common genetic variants
associated with increased plasma TG increase the risk of coronary artery disease, again suggesting
a causal relationship. This included single-nucleotide polymorphisms associated with a minimal
change in LDL cholesterol (35). Although plasma TGs are associated with atherosclerotic risk
and remnant particles have atherogenic properties in experimental models, clinical trials have not
yet conclusively demonstrated that lowering of plasma TG directly contributes to lowered risk of
atherosclerosis.
6. GENETIC CONDITIONS
A number of monogenic disorders are known to substantially alter circulating chylomicron con-
centration. Moreover, in recent years, genome-wide association studies have revealed common
genetic variants that associate with plasma TG concentration. Here we briefly review the genetic
determinants of circulating chylomicron and TG concentration.
6.1. Monogenic Conditions with Increased Circulating Chylomicrons

6.1.1. Chylomicronemia (Frederickson hyperlipoproteinemia type 1). Elevated concentra-
tion of fasting chylomicrons is a key feature of these monogenic disorders. It is characterized by
very high plasma TG concentration and risk of developing acute pancreatitis. Causative muta-
tions, usually homozygous or compound heterozygous, have been identified in genes—namely
LPL, APOC2, APOA5, LMF1, and GPHIB1—that regulate the clearance of chylomicrons (61).
LPL encodes lipoprotein lipase, the main enzyme involved in the hydrolysis of chylomicrons.
APOC2 is an essential cofactor for LPL activity, whereas ApoA5 is important for chylomicron hy-
drolysis. Lipase maturation factor 1 (encoded by LMF1) is an ER protein that post-translationally
activates LPL. Glycophosphatidylinositol HDL-binding protein-1 (encoded by GPHIB1) trans-
fers LPL across and tethers it to the endothelial surface (77). Although these mutations affect the
clearance of TRLs such as chylomicrons, they may also indirectly affect the production of these
lipoproteins. Ooi et al. (113) demonstrated that patients with LPL homozygous mutations have
reduced production of TRL ApoB-100 from the liver. A plausible explanation may be that due to
reduced LPL activity and hydrolysis of TRL, circulating FFA are likely reduced, although this was
not formally measured in this study. Reduced circulating FFA is also likely to reduce production of
chylomicrons (42), but this needs to be formally demonstrated. Interestingly, despite the elevated
plasma TGs, these patients appear not to be at increased risk of atherosclerotic disease and may
even be protected from it (77), although this issue remains controversial. This may be due to the
large size of the chylomicron particles and reduced concentration of remnant particles, which are
thought to be atherogenic.
6.18 Dash et al.
6.2. Common Genetic Variants Associated with Increased Plasma Triglycerides

Recent genome-wide association studies have found a number of genetic variants associated with
increased plasma TGs, either alone or in combination with elevations in other lipoproteins such
as LDL (61). Some of these variants are in or near genes also implicated in monogenic disor-
ders of hypertriglyceridemia, such as APOA5, LPL, ANGPTL3, and APOB, and are postulated to
affect chylomicron clearance, whereas others are implicated in insulin action and carbohydrate
metabolism and may therefore indirectly affect chylomicron production [CHREBP, glucokinase
regulatory protein (GCKR), and GALNT2 (uDP-N-acetyl-alpha-D-galactosamine:polypeptide N-
acetylgalactosaminyltransferase)] (61), whereas the potential mechanisms by which some of the
variants affect TG are unknown. Whether these variants definitively affect production of chylomi-
crons has not been investigated.
Desmarchelier and colleagues (34) recently performed whole-genome genotyping in healthy
volunteers after a fat meal to assess variants associated with postprandial chylomicron concen-
tration. A total of 126 candidate genes were selected based on association with plasma TG in
previous GWAS studies as well as pathway analysis. Forty-two single-nucleotide polymorphisms
in 23 genes were identified, which explained ∼88% of the variability in postprandial chylomicron
response (34). It is unknown whether any of these variants are directly associated with increased
chylomicron production, although some of the genes could potentially affect fatty acid uptake and
TG synthesis [for example, CD36, ELOVL5 (which encodes fatty acid elongase 5), and SLC27A5
and SLC27A6 (both of which encode a fatty acid transporter)]. Others are implicated in chylomi-
cron clearance (LPL, APOB, APOA5, LIPC), insulin and carbohydrate metabolism (IRS1, INSIG2,
TCF7L2), HDL function (APOA1 and ABCA1), and appetite and body weight regulation (MC4R).
6.3. Monogenic Causes of Hypotriglyceridemia

6.3.1. Chylomicron retention disease. This autosomal recessive condition is characterized
by impaired chylomicron secretion with retention of dietary lipid within the enterocytes and
steatorrhea. ApoB-48 is absent in the circulation. Patients usually present with malabsorption,
steatorrhea, and failure to thrive (150). Causative mutations have been identified in SARB1, which
affects the intracellular trafficking of chylomicrons in COPII vesicles (78).
6.3.2. Abetalipoproteinemia. This autosomal recessive disorder is characterized by very low

plasma LDL cholesterol and TG. Loss-of-function mutations in MTP predicted to impair the
lipidation and secretion of both ApoB-48 in the gut and ApoB-100 in the liver have been identi-
fied (150). As a consequence of malabsorption of fat-soluble vitamins A, D, and E, neurological
complications as well as hepatic steatosis are major features of this disorder (150). Interestingly,
despite the hepatic steatosis, insulin resistance is not a feature of this disorder (4).
6.3.3. Hypobetalipoproteinemia. This disorder is associated with low plasma TG and LDL
cholesterol and hepatic steatosis, but the phenotype is less severe than that of abetalipoproteine-
mia (150). Neurological features are usually absent in this disorder. Causative loss-of-function
mutations have been identified in ApoB that are predicted to lead to reduced production of
VLDL and/or chylomicrons (150). Kinetic studies have confirmed that patients with heterozy-
gous mutations due to premature stop mutations predicted to encode a truncated ApoB-48 have
reduced TRL ApoB-48 production with no effect on the fractional catabolic rate (66). Famil-
ial hypobetalipoproteinemia has also been reported with loss-of-function mutations in ANGPTL3
(encoding the angiopoietin-like 3 protein, which inhibits lipoprotein and endothelial lipase) (103).
Loss-of-function mutations in other members of the angiopoietin-like protein family have also
been associated with low plasma TG concentration (132).
In summary, single-gene disorders with large effect sizes as well as multiple genetic variants
with small effect sizes can alter plasma TG and chylomicron concentrations.
7. FUTURE DIRECTIONS
7.1. Gut Microbiota
In recent years, a number of studies have demonstrated that altered gut microbiota composition
may directly contribute to conditions such as obesity and insulin resistance (128, 157, 160). No
study has directly assessed the effects of gut microbiota on chylomicron production. Based on
the intricate link between obesity, insulin resistance, and chylomicron production in humans, one
might expect altered gut microbiota to be a potential contributor to altered chylomicron kinetics
(Figure 3).
7.2. Genetics
A number of genetic variants have been associated with plasma TG and chylomicrons, but the
mechanisms by which they affect TG and chylomicron concentration have not always been estab-
lished and warrant further investigation. Additionally, many studies assessing genetic determinants
of plasma TGs are performed in the fasted state. Since chylomicron concentrations are highest
postprandially, studies carried out in the fed state may be informative. Micro-RNAs have been
implicated in the regulation of VLDL production by the liver (126, 145). Because the gut and
liver share many similarities in the regulation of TRL production, it is plausible that micro-RNAs
are potential regulators of chylomicron secretion.
7.3. Neural Regulation

Some animal studies have indicated that the actions of glucose and glycine in the CNS can regulate
VLDL production by the liver (85, 178). In addition, the CNS action of GLP-1 may also contribute
to reduced chylomicron production (45). Whether the CNS-mediated actions of other hormones
can regulate chylomicron production directly remains to be explored (Figure 3). Rodent studies
and some human studies have indicated that the CNS can regulate peripheral insulin sensitivity
(31, 82, 112, 121) and thus potentially indirectly affect chylomicron production, although this has
not been formally addressed.
7.4. The Physiological Role and Regulation of Enteral Lipid Storage

The gut is capable of storing dietary lipids that can subsequently be mobilized, as discussed in
Section 4. Factors regulating the storage of dietary lipids are largely unknown. Further, the rel-
evance of this process in normal physiology and its contribution to postprandial hypertriglyc-
eridemia are largely unknown and warrant further investigation.
8. CONCLUSIONS
Rapid and efficient absorption of dietary lipid, its packaging into chylomicrons, and the release
of chylomicrons into the circulation are essential for maintenance of the body’s nutritional
state and metabolic homeostasis. Factors beyond dietary lipid ingestion regulate this process.
6.20 Dash et al.
Dysregulation of this process is seen in common human diseases such as insulin resistance and
type 2 diabetes. This dysregulation contributes to the postprandial hypertriglyceridemia often
seen in these diseases, which is a risk factor for atherosclerosis. Pharmacological targeting of
lipid absorption and chylomicron production may ameliorate this risk but thus far has been
associated with unacceptable side effects related to fat malabsorption. Although many factors such
as diet, genetics, hormones, drugs, nutraceuticals, and circadian rhythms regulate the process
of lipid absorption and chylomicron production, many other facets of its regulation remain
to be explored (Figure 3). Unraveling the complex metabolic process of fat absorption and
chylomicron production may identify potential novel therapeutic targets, which may ultimately
safely reduce the morbidity and mortality associated with these conditions.
SUMMARY POINTS
1. Dietary fat is incorporated into apolipoprotein-B48-containing chylomicrons and se-

creted into the circulation.
2. The assembly, secretion, and clearance of chylomicrons is a highly regulated process

influenced by circulating factors, diet, genetic factors, drugs, bariatric surgery, circadian
rhythms, and potentially gut microbiota and neural regulation.
3. Increased chylomicron production and reduced clearance are seen in highly prevalent
conditions such as obesity, insulin resistance, and type 2 diabetes.
4. Chylomicrons undergo lipolysis to yield chylomicron remnant particles that are poten-
tially atherogenic.
5. Increased chylomicron and chylomicron remnant concentration may contribute to the
increased atherosclerosis seen in obesity, insulin resistance, and type 2 diabetes. Reducing
chylomicron production may ameliorate the risk of atherosclerotic disease.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This work was supported by an operating grant (to G.F.L.) from the Canadian Institutes of Health
Research. G.F.L. holds the Sun Life Financial Chair in Diabetes and the Drucker Family Chair
in Diabetes Research. S.D. is the recipient of a Focus on Stroke 12 Fellowship Award from the
Heart and Stroke Foundation of Canada. C.M. is the recipient of a postdoctoral fellowship award
from the Banting & Best Diabetes Centre, University of Toronto. We are indebted to Brenda
Hughes, Patricia Harley, and Kris Puzeris for their nursing assistance and Linda Szeto for her
technical assistance in quoted studies performed by our group. We also thank Dr. Mahmood
Hussain, SUNY Downstate Medical Center, New York for providing the template for the figures
in the manuscript.
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NU35CH06-Lewis ARI 6 May 2015 11:15

Review in Advance first posted online

still occur before final publication

New Insights into the

Satya Dash,1,2 Changting Xiao,1,2

Cecilia Morgantini,1,2 and Gary F. Lewis1,2

Annu. Rev. Nutr. 2015. 35:6.1–6.30 Keywords

3.2. Hormonal, Local, and Circulating Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.11

4. THE GUT AS A LIPID STORAGE ORGAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.16

6.2 Dash et al.

2. OVERVIEW OF DIETARY LIPID ABSORPTION AND CHYLOMICRON

2.1. Absorption of Dietary Triglyceride

www.annualreviews.org • Regulation of Chylomicron Production 6.3

Fatty Fatty AGPAT 1–5

Monoacylglycerol Monoacylglycerol Diacylglycerol

L-FABP: liver fatty

6.4 Dash et al.

Free fatty acids Cholesterol Cholesterol

MTP MTP B48 TG (L-FABP)

www.annualreviews.org • Regulation of Chylomicron Production 6.5

2.4. Chylomicron Synthesis

6.6 Dash et al.

2.5. Chylomicron Clearance from the Circulation

www.annualreviews.org • Regulation of Chylomicron Production 6.7

Genetic variants Circulation factors

? Microbiota ? Neural regulation

3. REGULATION OF CHYLOMICRON PRODUCTION

3.1. Nutritional Factors

6.8 Dash et al.

3.1.2. Carbohydrates. Epidemiological studies have reported an association between plasma

www.annualreviews.org • Regulation of Chylomicron Production 6.9

6.10 Dash et al.

3.2. Hormonal, Local, and Circulating Factors

3.2.3. Glucagon-like peptide-1. Glucagon-like peptide 1 (GLP-1) is encoded by the

www.annualreviews.org • Regulation of Chylomicron Production 6.11

6.12 Dash et al.

3.3. Pharmacological Agents, Nutraceuticals, and Other Treatments

www.annualreviews.org • Regulation of Chylomicron Production 6.13

6.14 Dash et al.

postprandial hypertriglyceridemia. However, nausea, vomiting, and diarrhea were seen in a

3.4. Circadian Regulation of Chylomicron Secretion

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4. THE GUT AS A LIPID STORAGE ORGAN

6.16 Dash et al.

5. PLASMA CHYLOMICRON CONCENTRATION IN INSULIN

5.1. Chylomicrons in Insulin Resistance and Type 2 Diabetes

5.2. Chylomicrons and Atherosclerosis

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6.1. Monogenic Conditions with Increased Circulating Chylomicrons

6.18 Dash et al.

6.2. Common Genetic Variants Associated with Increased Plasma Triglycerides

6.3. Monogenic Causes of Hypotriglyceridemia

6.3.2. Abetalipoproteinemia. This autosomal recessive disorder is characterized by very low

www.annualreviews.org • Regulation of Chylomicron Production 6.19

7.3. Neural Regulation

7.4. The Physiological Role and Regulation of Enteral Lipid Storage

6.20 Dash et al.

1. Dietary fat is incorporated into apolipoprotein-B48-containing chylomicrons and se-

2. The assembly, secretion, and clearance of chylomicrons is a highly regulated process