Regulation of
Lipid metabolism
Objective
• At the end of this lecture, student will be able to
– Explain hormonal regulation of lipid
metabolism
– Explain fatty acid biosynthesis and
its regulation
– List the factors involved in
regulation of lipid metabolism
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
Regulation of Lipid Metabolism
• Regulation – in response
to the differing energy needs and dietary states of an organism
• Pancreatic
a 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 FA oxidation
Lipid Metabolism
Main processes:
• Digestion,
absorption, and transport of dietary fat
• Generation
of metabolic energy from fat: a) lipolysis, b) β-oxidation
• Storage of excess fat in adipose tissue
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
• 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
Regulation at the Level of LPL
• In the adipose tissue, the amount
of LPL is increased by
feeding/ insulin and
decreased by starvation
• 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)
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 (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
Regulation at the Level of Hormone- Sensitive Lipase
• Norepinephrine, epinephrine, and glucagon released during physical
exercise, stress, or fasting stimulate lipolysis
through the β-receptors, cAMP, PKA (Protein
Kinase A), and HSL(Hormone Sensitive Lipase)
Þ blood FA levels
Þ stimulation of β-oxidation in other tissues (liver,
muscle)
Þ stimulation of production of ketone bodies in the liver
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 Þ perilipin detaches from
the fat droplet, while lipase binds to the fat droplet
Insulin is released after eating and signals the abundance
of dietary nutrients (Glucose, Fatty acids and Amino acids), 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
Glucocorticoids, growth hormone, and the thyroid hormones
facilitate lipolysis by inducing the synthesis of lipolytic proteins:
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
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
• 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 Þ β-oxidation is inhibited when FA synthesis
is active
– 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 Þ stimulation of β-oxidation
FA Biosynthesis
• On a high-carbohydrate diet 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)
• The
formation of malonyl-CoA from acetyl-CoA is an irreversible process, catalyzed
by acetyl-CoA carboxylase – a
multifunctional polypeptide.
• It
contains a biotin prosthetic group covalently bound to the amino group of a Lys
residue in one of the 3 polypeptides (or domains) of the enzyme molecule.
• The
two-step reaction catalyzed by this enzyme -The carboxyl group, derived from
bicarbonate (HCO3), is first transferred to biotin in an ATP dependent
reaction. The biotinyl group serves as a temporary carrier of CO2, transferring
it to acetyl-CoA in the second step to yield malonyl-CoA.
• Mainly at the level of acetyl-CoA
carboxylase (ACC):
• The
long carbon chains of fatty acids are assembled in a repeating four-step
sequence.
• A
saturated acyl group produced by this set of reactions becomes the substrate for
subsequent condensation with an activated malonyl group.
• With
each passage through the cycle, the fatty acyl chain is extended by two
carbons.
• When
the chain length reaches 16 carbons, the product (palmitate,) leaves the cycle.
• Carbons
C-16 and C-15 of the palmitate are derived from the methyl and carboxyl carbon
atoms, of an acetyl-CoA used directly to prime the system at the outset; rest
of the carbon atoms are derived from acetyl-CoA via malonyl-CoA
• Carbons
C-16 and C-15 of the palmitate are derived from the methyl and carboxyl carbon
atoms, of an acetyl-CoA used directly to prime the system at the outset; rest
of the carbon atoms are derived from acetyl-CoA via malonyl-CoA
• Both
the electron-carrying cofactor and the activating groups in the reductive
anabolic sequence differ from those in the oxidative catabolic process –the
reducing agent in the synthetic sequence is NADPH and the activating groups are
two different enzyme-bound OSH groups.
• All
the reactions are catalyzed by a multienzyme complex, fatty acid synthase.
The overall process of palmitate synthesis
The fatty acyl chain grows by two-carbon units donated by
activated malonate, with loss of CO2 at each step.
The initial acetyl group is shaded yellow, C-1 and C-2 of
malonate are shaded pink,and the carbon released as CO2 is shaded green.
After each two-carbon addition,reductions convert the
growing chain to a saturated fatty acid of four, then six, then eight carbons,
and so on. The final product is palmitate .
Regulation of fatty acid synthesis
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
• 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)
• 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
Regulation of ACC – Overview
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)