The document summarizes lipid metabolism, including the digestion and absorption of lipids in the mouth, stomach, and small intestine. It describes the roles of lingual lipase, gastric lipase, pancreatic lipase, and bile salts in breaking down triglycerides. It also covers the absorption of lipids and their transport as chylomicrons, as well as the fate of absorbed lipids and the regulation and oxidation of fatty acids via beta-oxidation in the mitochondria.

1. Lipids Metabolism
Digestion and absorption of lipids

2. In the mouth
• Triglycerides accounts for 90% of dietary lipids.
• In the mouth, the lingual lipase (pH range 2.0-7.5)
is specific for the ester bond number three of
triglycerides. Digestion of triglycerides in the mouth
by lingual lipase is limited because food remains
short time in the mouth and lipids have low
solubility.
• Triglycerides lingual lipase Fatty acids +1,2
diacylglycerol

3. In the stomach
• In the stomach, the gastric lipase is secreted
which has the same activity of lingual lipase.

4. In the small intestine
• Small intestine is the major site of lipid digestion,
because the lipids are emulsified (Emulsification is
broken down of large lipid particles into small
particles which lead to increase the surface area of
lipids exposed to lipase) by bile salts that are
released from the gallbladder.

6. In the small intestine
• This increases the available surface area of the
lipids for pancreatic lipase and colipase (colipase
is a protein secreted by pancreas which is
important for the activity of pancreatic lipase by
binds the lipase at a ratio of 1:1, and anchors it at
the lipid-aqueous interface) to bind and to digest
the triglycerides. Pancreatic lipase is specific for the
ester bonds number one and three of triglycerides.

7. In the small intestine
• The product of fat digetion :
• 72% of ingested triglycerides are partially hydrolyzed
into 2 fatty acids and 2-monoacylglycerol.
22% of ingested triglycerides are completely
hydrolyzed into glycerol and 3 fatty acids.
6 % of ingested triglycerides are partially hydrolyzed
into 2 fatty acids and 1-monoacylglycerol.

9. Digestion of Cholesterol Esters and
Phospholipids
• Most cholesterol in the diet is in the form of
cholesterol esters. Cholesterol ester is hydrolyzed
by cholesterol esterase into free cholesterol and
one fatty acid. Phospholipids are hydrolyzed by
phospholipase A2 which remove fatty acid ester
bond number two.

11. Absorption of lipids
• Absorption of lipids take place in jejunum and
ileum. Short chain fatty acids and glycerol are
water soluble so that absorbed directly into
portal circulation to the liver.

12. Absorption of lipids
• The monoacylglycerols, long-chain free fatty acids,
cholesterol and lysophospholipids combine with
bile salt to form micelles . These micelles carry the
products of lipid digestion and fat soluble vitamins
to the brush border of mucosal cells where they are
absorbed into intestinal epithelium. Within the
intestinal epithelium,1-monoacylglycerols are
hydrolyzed to fatty acids and glycerol and 2-
monoacylglycerols are re-acylated to triglycerides
by long-chain fatty acids.

14. Absorption of lipids
• Fat-soluble vitamins, triglycerides, cholesterol and
phospholipids are combined with apolipoprotein
B48 to form chylomicrons which enter lymphatic
vessels to the circulation.

16. Fate of absorbed lipids
• Fat absorbed from the diet into blood as
chylomicrons. Chylomicrons give the plasma a
milky appearance, triglycerides of chylomicrons are
broken down by lipoprotein lipase (is located on
the walls of blood capillaries and required
apoprotein C-II and phospholipids for its activity)
into glycerol and Free fatty acids. After hydrolysis
of triglycerides, chylomicrons are called
chylomicron remnants which are taken up by the
liver by endocytosis.

17. Fate of glycerol
• Glycerol can be used to:
• 1-Formation of glucose by gluconeogenesis
• 2-production of energy by glycolysis
• 3- Synthesis of triglycerides by lipogenesis in liver.

18. Fate of free fatty acids
• Free fatty acids can be used to:
• 1-Formation of triglycerides of depot fat (adipose
tissue) by lipogenesis.
• Approximately 80% of adipose tissue is triglyceride
and about 90% of an adipocyte is triacylglycerol.
• 2- Formation of acetyl CoA to produce energy by
Krebs cycle.
• 3-Odd number fatty acids produce propionyl CoA to
synthesize glucose.
• 4-Synthesis of other compound e.g. prostaglandins.

19. Lipolysis in adipose tissue
• Lipolysis is the breakdown of triglycerides into free
fatty acids and glycerol.Triglycerides stored in
adipose tissue are hydrolyzed when there is stress
or in energy deficient conditions like starvation or
diabetes.

20. Lipolysis in adipose tissue
• Steps of lipolysis
1-Hormone sensitive lipase present in adipose tissue
converts triglycerids to di or monoglycerides and
fatty acids (hormone sensitive lipase remove the
fatty acid in ester bond number three and number
one
2- Di or monoglyceride lipase converts mono or
diglyceride to free fatty acids and glycerol.

21. Regulation of lipolysis by
hormones
• Lipolysis in adipose tissue is under hormonal
control, hormones like epinephrine, nor
epinephrine, glucagon, adrenocorticotropic
hormone (ACTH), melanocyte-stimulating
hormones (MSH), thyroid-stimulating hormone
(TSH), growth hormone (GH) increase lipolysis by
activation hormone sensitive lipase through
increasing cAMP level whereas insulin inhibits
lipolysis by inhibition hormone sensitive lipase
through decreasing cAMP level.

23. Oxidation of saturated fatty acids
• Lipids have high energy content about 2.25 times
in comparison with carbohydrates and protein.
Lipid can be stored without water of hydration,
which is not possible with glycogen ( 1 gram of
glycogen needs 2 grams of water for storage).Lipid
stores are greater compared to glycogen, for
example a 70 kg individual may have lipid store of
about 15 kg but his glycogen store is about only
0.317 kg.

24. Oxidation of saturated fatty acids
• The oxidation of fatty acids consist of three
stages:
• A-Activation of fatty acids in the cytosol
• B- Transport of activated fatty acids into
mitochondria
• C- β-oxidation of fatty acids in the mitochondria
matrix

25. Oxidation of saturated fatty acids
• A-Activation of fatty acids
• Activation of fatty acids is catalyzed by acyl-CoA
synthetase in presence of ATP to form acyl-CoA.
• Free fatty acid + CoA + ATP acyl-CoA synthetase
acyl-CoA +AMP+PPi

26. Oxidation of saturated fatty acids
• B-Transport of Fatty acyl-CoAs into mitochondria
• Long chain acyl-CoA is impermeable to inner
mitochondrial membrane,so that carnitine shuttle
transfers acyl-CoA from outer mitochondrial
membrane into matrix of mitochondria. Liver and
kidney synthesizes carnitine from lysine.

27. Oxidation of saturated fatty acids
• Steps of carnitine shuttle
• Step-1
• Acyl-CoA is transferd to carnitine to form acyl carnitine by
carnitine palmitoyl transferase-I , which present in the outer
mitochondrial membrane and it regulates entry of fatty acids into
mitochondria.
• Step-2
• Acyl carnitine is translocated into matrix of mitochondria by
carnitine-acyl carnitine translocase which present in inner
mitochondrial membrane.
• Step-3
• Acyl group of acyl carnitine is liberated as acyl-CoA by carnitine-
palmitoyl transferase-II present inside inner mitochondrial
membrane.

29. Oxidation of saturated fatty acids
• C-β-oxidation
• Beta oxidation is the process by which fatty acids are
broken down in mitochondria and/or in peroxisomes to
generate Acetyl-CoA. Fatty acid oxidation occurs in the
mitochondria of all types of cells like liver, heart, adipose
tissue, kidney, lung, skeletal muscle and to some extent in
brain except red blood cells. It is called β-oxidation,
because The chain of fatty acid is broken between the α-
carbon atom(number 2)- and β-carbon atom (number 3).

30. Steps of β-oxidation
• Step-1
• Removal of two hydrogen atoms from the α and β carbon atoms of
acyl-CoA, by acyl-CoA dehydrogenase in presence of FAD to
produce Δ2-trans-enoyl-CoA and FADH2.
• Step-2
• Water is added to saturate the double bond to form L- β-
hydroxyacyl-CoA, by enoyl-CoA hydratase.
• Step-3
• Conversion of β-hydroxy acyl-CoA in presence of NAD+ to β-keto
acyl-CoA and NADH+H+ by β-hydroxy acyl-CoA
dehydrogenase.

31. Steps of β-oxidation
• Step-4
• Splitting of β-keto acyl-CoA at α and β-carbon
atoms by β-keto acyl-CoA thiolase to produce
one acetyl-CoA and a new acyl-CoA which is
shorter than the original acyl-CoA molecule by
two carbon atoms. The new acyl-CoA formed in
the cleavage reaction reenters the β-oxidation at
step-1 until it is completely oxidized to acetyl-CoA.
Acetyl-CoA which produced are oxidized in citric
acid cycle to produce energy.

33. Calculation of energy produced by
stearic acid oxidation
• Stearic acid is a 18-carbon fatty acid and enters β-oxidation 8 times
producing 9 acetyl-CoA molecules, and each β -oxidation cycle
generates one FADH2 and one NADH. Therefore, the products of β
-oxidation of stearyl-CoA are 9 acetyl-CoA, 8 FADH2 and 8 NADH.
• 1. Number of ATP generated by citric acid cycle oxidation of 9
Acetyl-CoAs (9 × 12) = 108
• 2. Number of ATP generated by respiratory chain oxidation of 8
NADH= (8 × 3) = 24
• 3. Number of ATP generated by respiratory chain oxidation of 8
FADH2= (8 × 2) = 16
• 4-Two ATP are used by acyl CoA synthetase
= - 2ATP
• Total = 146

34. Note
• 1-Fatty acids with an odd number of carbon atoms are oxidized by the pathway
of β-oxidation, producing many acetyl-CoA, and one propionyl-CoA. propionyl-
CoA is converted to succinyl-CoA, a constituent of the citric acid cycle.
Propionyl-CoA can be converted to glucose, so that an odd-chain fatty acid is
glucogenic but not even chain fatty acid.
• 2-Triacylglycerols are the most storage form of energy in the body due to:
• a-Triacylglycerols or triglyceride contain more energy(9 Kcal/g) than
carbohydrates and proteins which contain 4 kcal/g. This is because fatty acids
• contain large amount of hydrogen, for example one mole of glucose (6 carbon
atoms) weight180 grams contains 12 gram of hydrogen ,while on mole of fatty
acid called caproic acid (6 carbon atoms) weight 116 grams contains 12 gram of
hydrogen.
• b-Triacylglycerols are non-polar, so it stored without water (anhydrous form),
while glycogen is polar, so it stored with water (one gram of glycogen combines
with 2 grams of water).

35. Regulation of Beta Oxidation
• 1- During fasting glucagon level increases and
stimulates lipolysis which lead to increase free fatty
acids which are converted to acyl-CoA which
inhibits lipogenesis and stimulate β-oxidation.
• 2-During feeding , insulin level increases and
stimulates lipogenesis (by activating acetyl-CoA
carboxylase) and inhibits β-oxidation (because
insulin activates acetyl-CoA carboxylase which lead
to formation of malonyl-CoA which inhibits
carnitine palmitoyltransferase I, important enzyme
for β-oxidation).

37. α-oxidation
• α-oxidation is used for initial oxidation of branched
chain fatty acids in peroxisome , branched chain
fatty like phytanic acid (20 carbons) found in plant
foods (derived from chlorophyll of plants), fatty
acids undergo to hydroxylation at α-carbon, then
decarboxylation of carbon number 1to form
pristanic acid (19 carbons) which enters β-oxidation.

38. α-oxidation
• Steps
• 1- Phytanic acid undergoes to hydroxylation at α-
carbon by phytanic acid α-hydroxylase to form α-
hydroxy phytanic acid.
• 2- α-hydroxy phytanic acid is converted to pristanic
acid by phytanic acid α-oxidase. Pristanic acid then
enter in β-oxidation.
• Note: Phytanic acid not oxidize by β-oxidation due
to presence of methyl group attached with β-
carbon(branches at odd-numbered carbons are not
suitable substrates for β-oxidation).

40. α-oxidation
• Important of α-oxidation
• 1- Oxidation of branched chain fatty acid phytanic
acid.
• 2-Formation of odd chain fatty acids to synthesis
sphingolipids
• 3-Formation of α- hydroxy fatty acids like
cerebronic acid which is important for brain
cerebrosides

41. Medical importance
• 1-Refsum's disease
• Refsum's disease is autosomal recessive disorder
due to a deficiency of phytanic acid α-hydroxylase
in peroxisome, which lead to accumulation of
phytanic acid in blood and tissues. The main
symptoms are neurologic damage which lead
to cerebellar degeneration, and peripheral
neuropathy, ataxia, difficulty hearing, and eye
problems. It is treated by avoiding consumption of
food containing phytanic acid (plants, animal fats)

43. Ω -oxidation
• ω-oxidation (minor pathway for long and very long
fatty acids oxidation in endoplasmic reticulum),
fatty acids undergo to hydroxylation at ω-carbon
(end methyl group of fatty acid), then oxidation to
form dicarboxylic acid, which undergoes β-oxidation
in peroxisome from both ends.It is important in
case of defective β-oxidation in mitochondria.
• Note: β-oxidation of very long fatty acids is low in
mitochondria

45. Oxidation of very long fatty acids
in peroxisomes
• Very-long-chain fatty acids undergo initial β-
oxidation in peroxisomes to shorten fatty acids, for
complete β-oxidation in mitochondrion. The FADH2
which produces in β-oxidation in peroxisomes not
produce ATP but is oxidized by molecular oxygen
(O2) to produce hydrogen peroxide (H2O2) which
breakdown by catalase to water.

46. Medical importance
• 1-Zellweger syndrome (cerebrohepatorenal
syndrome) is an autosomal recessive systemic
disorder due to defect in transport of very long fatty
acids across the peroxisomal membrane, or to the
absence of peroxisomes which lead to acumulation
of very long fatty acids in the brain, liver and kidney.
It is characterized by severe neurologic
dysfunction, craniofacial abnormalities, and liver
dysfunction. Most of affected individuals with
Zellweger syndrome may die within the first year of
life.

48. β -Oxidation of saturated odd
chain fatty acids
• The β-oxidation of saturated odd chain fatty acids
is the same of β-oxidation of saturated even chain
fatty acids but final three carbons which called
propionyl CoA (Propionyl CoA is also produced
during catabolism of some amino acids), is
converted to succinyl CoA by three steps:

49. β -Oxidation of saturated odd
chain fatty acids
• 1- Propionyl CoA is converted to D-methylmalonyl
CoA by propionyl CoA carboxylase.
• 2- D-Methylmalonyl CoA is converted to L-
Methylmalonyl CoA by methylmalonyl CoA
racemase .
• 3- L-Methylmalonyl CoA is converted to succinyl
CoA by methylmalonyl CoA mutase (vitamin B12
dependent. Succinyl CoA may enter citric acid cycle
to produce energy or converted to glucose.

51. β -Oxidation of unsaturated fatty
acids
• Oxidation of unsaturated fatty acids, provides less
energy than that of saturated fatty acids, because
unsaturated fatty acids contain less hydrogen. All
the reactions of β -Oxidation of unsaturated fatty
acids are the same of β -Oxidation of saturated
fatty acids, but the precence of duble bonds need
additional enzyme called isomerase , epimerase
and reductase to saturate the double bonds.

53. β -Oxidation of unsaturated fatty acids
• Calculation of energy produced by linoleic acid oxidation

54. Metabolism of Ketone bodies
• Ketone bodies are water-soluble compounds
produced when an excess amount of acetyl-CoA
arises from β-oxidation( ketone bodies formed
when oxaloacetate is not enough to react with
the large amounts of acetyl-CoA). Ketone bodes
are acetoacetic acid, β-Hydroxy butyric acid and
Acetone.

55. Ketogenesis
• Synthesis of ketone bodies is called ketogenesis. It
occurs during fasting state , starvation or diabetes
mellitus , because oxaloacetate is consumed to
form glucose by gluconeogenesis. Ketone body
synthesis occurs only in the mitochondrial matrix
in the liver but are important sources of energy for
many extrahepatic tissues, including brain, heart,
and skeletal muscle. Liver can not used ketone
bodies for energy production.

56. Steps of Ketogenesis
• Step-1
• Condensation of two acetyl-CoA molecules to form acetoacetyl-CoA by thiolase.
• Step-2
• Aceto acetyl-CoA condenses with one acetyl-CoA to form 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) by 3-hydroxy-3-methylglutaryl-CoA synthase.
• Step-3
• 3-Hydroxy-3-methylglutaryl-CoA lyase splits HMG-CoA to acetoacetate and
acetyl-CoA.
• Step-4
• β-hydroxy butyrate is formed from acetoacetate by reduction by
3-Hydroxybutyrate dehydrogenase.
• Step-5
• Spontaneous decarboxylation of aceto acetate produces acetone.

58. Regulation of keteogenesis
• 1-During fasting glucagon and epinephrine levels increase which lead to increase
lipolysis in adipose tissues by activating hormone sensitive lipase by increasing
cAMP (Glucagon and epinephrine activate adenyl cyclase which converts ATP to
cAMP), this lead to increase free fatty acids which enter β-oxidation and formation
large amount of acetyl CoA in liver which form keteone bodies.
• Note: Acetyl CoA during fasting prefer ketogenesis but not Krebs cycle due to
decrease oxaloacetate level because most oxaloacetate is converted to malate due
to precence of large amount of NADH as a result of β-oxidation and malate
transferee from mitochondria to cytosol for gluconeogenesis.
• 2-During feeding insulin level increase ,and inhibits lipolysis by inhabiting hormone
sensitive lipase by decreaseing cAMP (insulin activates phoshodiesterase which
converts cAMP to AMP),this lead to decrease β-oxidation and decrease
ketogenesis.
• 3-During diabetes mellitus, insulin is decrease or absent, this lead to increase
glucagon which activate lipolysis and β-oxidation and ketogenesis.

59. Ketolysis
• Degradation of ketone bodies is called ketolysis.
Heart, brain and skeletal muscle and other tissues
use ketone bodies for energy production during
prolonged fasting or starvation. Liver is unable to
use ketone bodies due to lack of enzymes of
ketolysis.It occurs in mitochondria.

60. Steps of Ketolysis
• Step-1
• Conversion of β-Hydroxy butyrate to acetoacetate by β-
Hydroxy butyrate dehydrogenase.
• Step-2
• Acetoacetate is activated by transfer of coenzyme A (CoA-
SH) from succinyl-CoA in presence of β-ketoacyl-CoA
transferase
• Step-3
• Thiolase cleaves aceto acetyl-CoA to two molecules of
acetyl-CoA. The acetyl-CoAs are oxidized by citric acid
cycle to produce energy.

62. Ketosis and ketoacidosis
• Ketosis and ketoacidosis
• Ketosis is accumulation of ketone bodies in blood
and ketoacidosis is excessive accumulation of
ketone bodies in blood which lead to decrease
blood pH. Ketoacidosis is most common in
untreated type 1 diabetes mellitus due to increase
lipolysis.

63. Calculation of energy produced by
oxidation of ketone bodies
A- β-Hydroxy butyric acid consist of four carbon atoms, which produce
2 acetyl-CoA, and gain 1 NADH from frist step of ketolysis.
1. Number of ATP generated by citric acid cycle oxidation of 2 Acetyl-CoAs (2 × 12) =
24
2. Number of ATP generated by respiratory chain oxidation of 1 NADH= (1 × 3) = 3
Total = 27 ATP
B- Acetoacetic acid consist of four carbon atoms, which produce 2 acetyl-CoA.
1. Number of ATP generated by citric acid cycle oxidation of 2 Acetyl-CoAs (2 × 12) = 24
Total = 24 ATP

67. Metabolism of Lipoproteins
• 1-Metabolism of Chylomicron
• Synthesis
• Chylomicron is the largest lipoproteins, produced in
small intestine. Triglycerides(TG) and cholesterol(C)
from dietary fat are coated with phospholipids and
apoA and apo B-48 to produce chylomicrons.
Chylomicron enters lymphatic vessels to the blood and
called nascent chylomicron. In the blood nascent
chylomicrons combines with apo C and apo E to form
mature chylomicron. It is responsible for the transport
of dietary (exogenous) lipids from intestine to the
tissues.

68. Metabolism of Chylomicron
• Breakdown
• Half-life of plasma chylomicron is less than an
hour in humans,triglycerides of chylomicrons
are broken down by lipoprotein lipase into
glycerol and Free fatty acids. After hydrolysis
of triglycerides, chylomicrons are called
chylomicron remnants which are taken up by
the liver by endocytosis through apo E
receptors.

70. Metabolism of Very low density
lipoprotein (VLDL)
• Synthesis
• Very low density lipoprotein is synthesized in liver,
its function is to transport endogenous lipids to the
extra hepatic tissues.In hepatocytes, synthesized
triglycerides combines with phospholipids,
cholesterol and apo B-100 to produce VLDL which
called nascent VLDL.VLDL enters the blood. In the
blood nascent combines with apo C and apo E to
form mature VLDL.

71. Metabolism of Very low density
lipoprotein (VLDL)
• Breakdown
• VLDL are broken down by lipoprotein lipase into
glycerol and Free fatty acids. After hydrolysis of
triglycerides, VLDL are called intermediate density
lipoproteins (IDL) or VLDL remnants which are
taken up by the liver by endocytosis through apo E
receptors. LDL may be produced in the blood from
VLDL remnants by removing apo E.

73. Metabolism of Low density lipoproteins( LDL)
Synthesis
• LDL transports cholesterol which synthesized in the
liver to extra hepatic tissues, and a high level of LDL
in blood considers as a risk factor for cardiovascular
diseases. LDL formed from VLDL remenant in the
blood by removing apo E.

74. Metabolism of Low density lipoproteins( LDL)
Synthesis
• Breakdown
• Extra hepatic tissues remove 30 % of LDL and
70 % is removed by liver by endocytosis
through apo B-100 receptors and in the cells
LDL are broken down by lysosomal enzymes.

75. Metabolism of high density lipoproteins( HDL)
• Synthesis
• High density lipoprotein is the smallest lipoproteins of
high density, produced in liver and intestine, it
transports cholesterol from the extra hepatic tissues,
to the liver and it acts as a reservoir for the apo C and
apo E required in the metabolism of chylomicrons and
VLDL. A high level of HDL in blood reduces the risk for
cardiovascular diseases. HDL is synthesized and
secreted from both liver and intestine and called
nascent HDL which is composed of cholesterol,
phospholipid and apo A, apo C and apo E. Nascent HDL
has flat discoid shape.

76. Metabolism of high density lipoproteins( HDL)
• In plasma cholesterol of HDL is esterified by
lecithin:cholesterol acyltransferase(LCAT) into
cholesterol esters (CE) and Cholesterol ester
formed by the action of LCAT moves from
periphery of HDL to the center of the discoid HDL,
and HDL becomes spherical shape.

77. HDL
• Breakdown
• The transport of cholesterol from the tissues to the
liver is known as reverse cholesterol transport and is
mediated by an HDL cycle. The smaller HDL3 accepts
cholesterol from the tissues via the ATP-binding
cassette transporter-1 (ABC-1).. After being accepted
by HDL3, the cholesterol is then esterified by LCAT,
increasing the size of the particles to form the less
dense HDL2. The cycle is completed by the re-
formation of HDL3, either after selective delivery of
cholesteryl ester to the liver via the SR-B1 or by
hydrolysis of HDL2 phospholipid and triacylglycerol by
hepatic lipase.

79. Cholesterol Metabolism
• Cholesterol Synthesis occurs in the cytoplasm of most tissues, but
the liver (50%),intestine, adrenal cortex, testis, and ovaries are the
most active. About 0.7 grams per day of cholesterol is synthesized
by the body. Cholesterol is synthesized from acetyl-CoA in precence
of NADPH and ATP. Acetyl-CoA produced from the break down of
carbohydrates, fats and amino acids. It is an essential structural
component of cell membrane, and it is a precursors of bile acids,
steroid hormones, and Vitamin D but a high level of blood
cholesterol is an indicator for heart diseases. All tissues containing
nucleated cells are able to synthesis cholesterol in the endoplasmic
reticulum and cytosol. Normal range of cholesterol in serum (140-
200 mg/dl) or (3.6-5.2 mmol/l).

82. Regulation of cholesterol
biosynthesis
• The rate limiting enzyme or the key enzyme of cholesterol
biosynthesis is HMG-CoA reductase.
• A-By changing the amount of enzyme by
• 1-Increase concentration of cholesterol in liver cells
reduces the synthesis of the HMG CoA reductase
• 2-Insulin and thyroid hormones induce synthesis
of the HMG CoA reductase (increase activity of
enzyme) but glucagon and glucocorticoids repress
or inhibit the synthesis of the HMG CoA reductase

83. Regulation of cholesterol
biosynthesis
• 3- Increase concentration of cholesterol and bile
acids in liver cells activate binding of enzyme to
Insig (insulin induced gene) protein which
accelerate breakdown of HMG CoA reductase by
ubiquitin-proteasome system

84. B-Covalent modification
• HMG-CoA reductase is active in dephosphorylated form
and inactive in phosphorylated form.
• 1-Increase AMP (decrease energy or during fasting)
inhibits cholesterol synthesis because AMP inhibits HMG-
CoA reductase by phosphorylation.
• 2-Glucacon and cholesterol inhibits cholesterol synthesis
because c-AMP inhibits HMG-CoA reductase by
phosphorylation.
• 3- Insulin stimulates cholesterol synthesis because insulin
stumulates HMG-CoA reductase by
dephosphorylation(activating phosphatase).

86. Medical importance
• 1-Statin drugs like, atorvastatin, and, lovastatin
(syntheses by fungi) , are used to decrease plasma
cholesterol levels in patients with
hypercholesterolemia because statin drugs are
analogs to HMG CoA, which act as competitive
inhibitors of HMG CoA reductase.

87. 2- Hypercholesterolemia
• Hypercholesterolemia mean increase plasma
cholesterol concentration more than 200 mg/dl or
more than 5.2 mmol/l.There are many causes lead
to hypercholesterolemia which include:

88. Hypercholesterolemia
• 1-Familial hypercholesterolemia (type II
hyperlipoproteinemia)
• Familial hypercholesterolemia is an autosomal
dominant disorder due to mutation in LDL
receptor which affects the structure and function
of the LDL receptor which lead to inhibit removing
LDL-cholesterol from circulation which lead to
hypercholesterolemia that leads to coronary
artery disease, atherosclerosis and myocardial
infarction (heart attack).

89. Hypercholesterolemia
• 2-Diabetes mellitus
• Diabetes mellitus may lead to
hypercholesterolemia because in diabetes mellitus,
insulin decreased or absent and glucagon
increased.Glucagon stimulate lipolysis and
oxidation of fatty acids which lead to formation
large amount of acetyl CoA which lead to increase
cholesterol synthesis.

90. Hypercholesterolemia
• 3- Hypothyroidism
• Low amounts of thyroid hormones
(hypothyroidism)lead to increased blood
cholesterol (hypercholesterolemia), due to
decrease the number of low-density lipoprotein
(LDL) receptors in hepatocyte membranes, which
lead to decrease uptake of cholesterol from the
blood and decrease excretion of cholesterol in
bile.

91. Hypercholesterolemia
• 4- Obstructive jaundice
• Obstructive jaundice lead to decrease the excretion of cholesterol
with bile juice.
• 5-Nephrotic syndrome (Nephrosis)
• Nephrotic syndrome is a group of diseases characterized by
massive proteinuria > 5 grams per day and hyperlipidemia, and
decrease albumin (low molecular weight excrete with urine) but
increase globulin (high molecular weight, not excrete with
urine).Globulin enters in the synthesis of lipoprotein which lead to
increase cholesterol and triglyceride.
• 6-Increase dietary carbohydrate , saturated fat, and cholesterol

92. Hypercholesterolemia
• Notes:
• 1-Diatery polyunsaturated fatty acids (PUFA) reduces the plasma
cholesterol level because polyunsaturated fatty increase the
number of LDL-receptors which lead to increase the removal of LDL-
cholesterol from circulation, also polyunsaturated fatty acids induce
synthesis of cholesterol 7α-hydroxylase
• which responsible for converting cholesterol to bile acids, while
dietary saturated fatty acids increase plasma cholesterol level
because saturated fatty decrease the number of LDL-receptors
which lead to decrease the removal of LDL-cholesterol from
circulation. So polyunsaturated fatty acids reduce the risk of
cardiovascular diseases.

93. Hypercholesterolemia
• 2- Polyunsaturated fatty acids increases fluidity of cell membrane which help in
binding of LDL-receptors to the cell membrane of cells but saturated fatty acids
decrease fluidity of cell membrane which inhibits the binding of LDL-receptors to
the cell membrane of cells.
• 3- Polyunsaturated fatty acids decrease plasma triglyceride by:
• a-Decreasing lipogenesis and decrease secretion of VLDL by inhibition of a sterol
regulatory element-binding protein (SREBP) transcription factor which regulate
the transcription of many genes involved in the cellular uptake and metabolism
of cholesterol and other lipids.
• b-Increase expression of lipoprotein lipase and decrease apoC-III (apoC-III is
important in synthesis of VLDL) lead to decrease triglyceride.
• c-Increase reverse transport of lipoprotein (from tissues to liver)
• 4-Dietary fiber in vegetables decreases the cholesterol absorption from the
• intestine.

94. Hypercholesterolemia
• 5-Plasma cholesterol is increases in
smokers(smoking lead to decrease HDL level
because smoking decrease synthesis of apoA-I
which is important in synthesis of HDL), obese
persons, lack of exercise, stress, consumption of
soft drink, so changes in the lifestyles will
decrease plasma cholesterol.
• 6-Trans fat increase the level of LDL and decrease
HDL

95. Hypocholesterolemia
• Hypocholesterolemia means low level of blood
cholesterol, there are many causes of
Hypocholesterolemia:
• 1-Liver cirrhosis
• 2-Hemolytic anemia
• 3-Hyperthyrodism ( due to increased LDL receptor
gene expression resulting in increased LDL
receptor-mediated catabolism of LDL particles).