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Lecture No. 18 Hormonal Regulation of Fatty Acid Biosynthesis

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Lecture No.

18
Hormonal regulation of fatty acid biosynthesis

• At the end of this lecture, student will be able to

– Explain hormonal regulation of lipid metabolism


– Explain fatty acid biosynthesis and its regulation
– Describe factors involved in regulation of lipid metabolism

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Faculty of Pharmacy ©M. S. Ramaiah University of Applied Sciences
Regulation in General

• A) Short term (response time of minutes or less):


– substrate availability
– allosteric interactions
– covalent modifications
(phosphorylation/dephosphorylation)

• B) Long-term (response time of hours or days):


– changes in the rate of protein (enzyme) synthesis or
breakdown

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Regulation of Lipid Metabolism

• Involves all the aforementioned mechanisms

• Regulation – in response to the differing energy needs and


dietary states of an organism

• Pancreatic  cells respond to the low blood glucose


concentration of the fasting and energy-demanding states by
secreting glucagon; the β cells respond to the high blood
glucose concentration of the fed and resting states by
secreting insulin

• Targets: enzymes of FA synthesis and oxidation

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Lipid Metabolism

• Main processes:

– 1) digestion, absorption, and transport of dietary fat

– 2) generation of metabolic energy from fat:


• a) lipolysis, b) β-oxidation

– 3) storage of excess fat in adipose tissue

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1) Absorption and Transport
• The main products of fat
digestion are free FA and
2-monoacylglycerols
(produced by the action of
pancreatic lipase)

• After absorption, FA is
activated to acyl-coenzyme A
(in the ER) which then reacts
with 2-monoacylglycerol to
form triacylglycerol

• In the ER, TGs are assembled


into chylomicrons that are
collected by the lymph and
carried to the blood stream

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Absorption and Transport

• TGs in chylomicrons are utilized by adipose tissue,


heart, skeletal muscle, lactating mammary gland
and, to a lesser extent, by the spleen, lungs, kidney.

• These tissues (but not the liver and brain!) express


lipoprotein lipase (LPL), attached to the surface of
the capillary endothelium, that hydrolyzes TGs to FA
and 2-monoacylglycerols; the products are taken up
by the cells

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Regulation at the Level of LPL

• In the adipose tissue, the amount of LPL is increased by


feeding/ insulin and decreased by starvation

X
• In contrast, the amount of LPL in heart is decreased by insulin
and increased by starvation

Dietary fat is directed mainly to the adipose tissue (for storage) in


the well-fed state but to the muscles during fasting (for oxidation)

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2 a) FA release from Adipose Tissue

• Hormone-sensitive lipase converts the fat stored in


adipose tissue into glycerol and FAs that are
transported to distant sites bound to serum albumin
(x liver and intestine release lipids in the form of
lipoproteins)

• Hydrolysis rate controls the concentration of FAs in


the blood and thus regulates FA oxidation

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Regulation at the Level of Hormone- Sensitive
Lipase

• A) Norepinephrine, epinephrine, and glucagon released


during physical exercise, stress, or fasting stimulate
lipolysis through the β-receptors, cAMP, PKA, and HSL
  blood FA levels

 stimulation of β-oxidation in other tissues (liver,


muscle)
 stimulation of production of ketone bodies in the
liver

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Mechanism

• In the resting state, the hormone-sensitive lipase is cytoplasmic and


the surface of the fat droplet is covered by the protein perilipin
• The cAMP-stimulated protein kinase A phosphorylates both perilipin
and lipase  perilipin detaches from the fat droplet x lipase binds

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• B) Insulin is released after Glc and AA
intake and signals the abundance of
dietary nutrients that are eligible for
storage

– Insulin inhibits HSL through


phosphodiesterase degrading cAMP

• Thus, the glucagon:insulin ratio is of


prime importance in regulation of lipid
metabolism

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C) Glucocorticoids, growth hormone, and the thyroid
hormones facilitate lipolysis by inducing the synthesis
of lipolytic proteins:

– glucocorticoids induce the synthesis of the


hormone-sensitive lipase

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2b) β-oxidation
• FAs are activated to acyl-
CoA by enzymes on the ER
membrane and
transported into the
mitochondrion by carnitine

• β-oxidation produces:
– acetyl-CoA, NADH,
FADH2

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Regulation of FA Oxidation
• A) Use of FAs by the tissues is proportional to the plasma FFA
level; therefore, FA oxidation is regulated at the level of HSL

– During fasting, the hormonal stimulation of adipose tissue


lipolysis (HSL) provides a large amount of FA

– FA are rather oxidized (than esterified) in the liver because of


an increased activity of CPT1 (see below)

– acetyl-CoA formed by β-oxidation is not used for biosynthesis


during fasting, its oxidation by the TCA cycle is minimal, and
it is used preferentially for the synthesis of ketone bodies

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After a
carbohydrate-rich
meal

During fasting
• B) Carnitine-palmitoyl transferase I (CPT1) is inhibited by
malonyl-CoA that is formed in the FA biosynthesis by acetyl-
CoA carboxylase  β-oxidation is inhibited when FA synthesis
is active

carboxylation
acetyl-CoA malonyl-CoA CPTI β-oxidation
ACC

– Thus, in the fed state, nearly all FAs entering the liver are esterified to
acylglycerols and transported out of the liver in the form of VLDL

– When FA level increases with the onset of starvation, ACC is inhibited


by acyl-CoA and malonyl-CoA decreases  stimulation of β-oxidation

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3) FA Biosynthesis

• On a high-carbohydrate diet when excess energy is


stored in the form of fat

• In the liver, lactating mammary gland, and, to a lesser


extent, in the adipose tissue

• FA synthesized in the liver are esterified to TGs which are


released in the form of VLDL

• VLDL are utilized by the action of LPL (mainly in the


adipose tissue)

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malonyl-ACP + acetyl-ACP

– CO2

reduction

dehydration

reduction

condensation with another malonyl 18


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Regulation of FA Synthesis

• Mainly at the level of acetyl-CoA carboxylase (ACC):

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1) Acetyl-CoA carboxylase is allosterically activated by
citrate and inhibited by CoA-thioesters of long-chain FAs
such as palmitoyl-CoA (well-fed liver has a higher citrate
level and lower acyl-CoA level than does the fasting liver)

Acetyl-CoA must be converted


to citrate to get from the
mitochondrion into cytoplasm

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Faculty of Pharmacy ©M. S. Ramaiah University of Applied Sciences
• 2) acetyl-CoA carboxylase is stimulated by insulin and
inhibited by glucagon and epinephrine
– glucagon and epinephrine mediate activation of the
cAMP-dependent protein kinase A, which inactivates ACC
– insulin antagonizes this cascade by inducing
phosphodiesterase that degrades cAMP
– insulin stimulates the synthesis of ACC and fatty acid
synthase, starvation inhibits it (long-term regulation)
• Thus, cAMP-dependent phosphorylation simultaneously
inhibits FA synthesis and stimulates FA oxidation (by
activation of HSL)

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Faculty of Pharmacy ©M. S. Ramaiah University of Applied Sciences
• 3) acetyl-CoA carboxylase is inhibited by phosphorylation
by the AMP-activated protein kinase (AMPK)

– AMPK is activated when the cellular energy charge is


dange-rously low (high AMP/ATP ratio) and helps the
cell to survive the energy shortage by switching-off
non-essential biosynthetic pathways such as FA
synthesis

– In the liver, AMPK is inhibited by insulin

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Regulation of ACC – Overview

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Long-term Regulation
• Starvation and/or regular exercise, by decreasing the
glucose concentration in the blood, change the body‘s
hormone balance

• This results in long-term increases in the levels of FA


oxidation enzymes (heart LPL) accompanied by long-
term decreases in those of lipid biosynthesis (ACC,
fatty acid synthase)

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Faculty of Pharmacy ©M. S. Ramaiah University of Applied Sciences
insulin
-
glucagon, + -
epinephrine
+
insulin +
- AMP-dependent -
insulin
phosphorylation

low insulin:glucagon ratio

FA oxidation

high insulin:glucagon ratio +


insulin
insulin -
FA synthesis
+
glucagon,
epinephrine
Summary: Effects of various hormones

Activity Insulin Glucagon


acetyl-CoA carboxylase
+ -
hormon-sensitive lipase
- +

Synthesis Insulin Glucagon


acetyl-CoA carboxylase
+ -
FA synthase
+ -

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Adipose tissue as an endocrine organ

Adipose tissue itself secretes various factors that


regulate glucose and lipid metabolism

•Two of the best-characterized are:


– leptin
– adiponectin

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Leptin

ob/ob mouse possesses muta-tions


in the gene encoding for leptin (
absence of functional
protein) and is massively obese

• Giving leptin to leptin-deficient patients results in a weight loss, but


administering leptin to obese patients does not have the same effect

• In fact, leptin concentration is increased in obese patients, but leptin


sensitivity is impaired (probably due to the development of leptin
resistance in many obese patients)

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Summary

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Faculty of Pharmacy ©M. S. Ramaiah University of Applied Sciences
Summary

• Hormone-sensitive lipase (HSL) is the enzyme that


hydrolyses triacylglycerides to free fatty acids from
fats
• Amount of LPL in heart is decreased by insulin and
increased by starvation
• Energy yield from a gram of fatty acids is
approximately 9 kcal

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