Download Biochemistry Lect 4 – N.42 – Lipid metabolism

Lipid Metabolism
Part 1
Dr. Basima S.Ahmed Jaff
Assist.Proffsor
PhD. Clinical Biochemistry
1-Pancreatic secretion enzymes
degrade dietary lipids in the small
intestine is hormonally controlled .
2-Cells in the mucosa of lower
duodenum and jejunum produce
peptide hormone, cholecystokinin
(CCK), in response to the presence of
lipids and partially digested proteins
entering these regions of the upper
small intestine. CCK acts on the
gallbladder (causing it to contract
and Release bile. decreases gastric
Motility.
3- secretin, in response to the low pH
of the chyme entering the intestine.
the pancreas andthe liver to release a
solution rich in bicarbonate .
 Lipid malabsorption
 Lipid malabsorption,
caused by disturbances
in lipid digestion
and/or absorption
disturbances can result
from several conditions,
including Cystic
Fibrosis (causing poor
digestion)
 TG Biosynthesis
FATTY ACID OXIDATION
Sources of fatty acids
(a) Dietary sourcesFatty acids formed from the digestion of
dietary lipids are carried to liver. From the liver, they are
transported to cell in bound form with albumin.
(b) Endogenous sources As mentioned above, free fatty acids
formed from body TG are used for energy production.
Though the plasma free fatty acid level is lower than blood
glucose level they are rapidly utilized by peripheral tissues.
The plasma free fatty acid (FFA) has life of 3-4 minutes.
SiteFatty acid oxidation occurs in the mitochondria of all
types of cells like liver, heart, adipose tissue, kidney, lung,
skeletal muscle and some extent in brain.
1. Oxidation by FAD
2. Hydration
3. Oxidation by NAD
4-cleavage
Regulation of β-oxidation
• Rate limiting step in the β-oxidation
formation of acyl-carnitine which is catalyzed by
carnitine-acyl transferase-I (CAT-I). CAT-I is
anallosteric enzyme. Malonyl-CoAis an inhibitor of
CAT-I.
– In well-fed state due to increased level of
insulin,concentration of malonyl-CoA increases
which inhibits CAT-I and leads to decrease in fatty
acidoxidation.
– In starvation, due to increased level of glucagon
concentration of malonyl-CoA decreases and
stimulates the fatty-acid oxidation
β-oxidation of a Fatty Acid with an Odd Number of Carbon
Atoms;
final β-oxidation cycle, of odd carbon fatty acids a
3 carbon fragment propionyl CoA is formed
rather than 2 carbon fragment acetyl-CoA.
• Propionyl-CoA is converted to succinyl-CoA a constituent of
citric acid cycle.
• Propionyl-CoA is carboxylated at the expense of an ATP to
yield the D-methylmalonyl-CoA; catalyzed by propionyl-CoA
carboxylase, a biotin enzyme.
Pathway of cholesterol biosynthesis
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THANKS/
Dr.Basema
Dr .Basima S. Ahmed Jaff
PhD.Clinical Biochemistry
• Lipoprotein metabolism
 Chylomicrone.
 VLDL, LDL
 HDL
Reverse Cholesterol Transport
• This is the process whereby excess cholesterol contained in extrahepatic tissue is taken
to the liver, through HDL metabolic cycle for utilization or excretion through the bile. •
The LCAT esterifies the cholesterol content of HDL
to prevent it from re-entering the cells. If the cholesterol is not esterified within the
HDL particle, the free cholesterol can leave the particle by the same route that it
entered. Thus esterification by LCAT serves to trap cholesterol within the lipoprotein,
preventing it from deposition in the tissues.
Significance of reverse cholesterol transport
• By reverse cholesterol transport cellular and lipoprotein cholesterol is delivered back
to the liver.
This is important because the steroid nucleus ofcholesterol cannot be degraded; and
the liver is the only organ that can remove excess cholesterol by secreting it in the bile
for excretion in the feces.
• Revese cholesterol transport prevents deposition of cholesterol in the tissues and is
thought to be antiatherogenic. An elevated HDL cholesterol (good cholesterol) level
decreases the risk of coronary heart disease.
Hypercholesterolemia
In a normal adult, the total plasma cholesterol ranges form 150–250 mg/100
ml.An ↑ in plasma cholesterol more than 250 mg/100 ml is known as
hypercholesterolemia and is seen in the following conditions:
1-Diabetes mellitus: ↓ of insulin,↑ rate of lipolysis. ↑ rate of lipolysis results
in↑FFAin circulation which in↑ acetyl-CoA. Excess of acetyl-CoA are diverted
for cholesterol biosynthesis
2. Hypothyroidism:This is due to ↓ in the HDLReceptors on hepatocyte in
hypothyroidism and due to ↓ synthesis of 7-α-hydroxylase that requires for
the conversion of cholesterol to bile acids. Thyroid hormone ↑ the
synthesis of 7-α-hydroxylase.
3. Obstructive jaundice:Due to ↓ excretion of cholesterol through bile.
4. Familial hypercholesterolemia:It is a genetic disease caused by deficiency or
malfunction of the LDL receptors. In the absence of these receptors, the liver
cannot take LDL and there is no release of cholesterol of LDL into the liver.
Therefore, they do not cause feedback inhibition of cholesterol synthesis and
lead to ↑ cholesterol formation
Fatty liver may occur due to:
1. Overproduction of triacylglycerol in liver.
2. Impaired synthesis of VLDL.
Case History
A 60-year-old woman was referred to a hospital. She
was noted to have hypertension. The plasma
cholesterol level was 390 mg/dL. An angiogram of the
right carotid artery demonstrated a narrowed lumen
and the concentration of LDL was elevated.
Questions
a. What is your probable diagnosis?
b. What is the normal plasma cholesterol level?
c. By which enzyme is cholesterol biosynthesis
regulated?
d. Which lipoprotein has protective effect against the
disorder?
Case History
A 30-year-old woman was hospitalized, with an
acute myocardial infarction. Her plasma
cholesterol and LDL level were highly elevated.
She was found to have familial
hypercholesterolemia.
Questions
a. How are LDL formed?
b. What apoprotein does LDL contain?
c. What is the function of LDL?
d. Why LDL is called bad cholesterol?
Ketone Bodies - formed
in the liver and oxidized in skeletal
and heart muscle and the renal
cortex. Brain adapts to use them
under starvation conditions
Regulation of Ketogenesis
1. Factors regulating lipolysis:FFA the precursors of
ketone bodies ↑ from lipolysis of TG in adipose tissue,
also regulate ketogenesis. The hormone glucagon
↑lipolysis which in turn ↑ketogenesis, whereas insulin
↓ lipolysis and ketogenesis.
2. Factors regulating β-oxidation of fatty acids
Carnitin acyl transferase I, regulates ketogenesis
during starvation. and formation of ketone bodies.
3. Factors regulating oxidation of acetyl-CoA:In turn,
the acetyl-CoA, formed in β-oxidation in liver
mitochondria, has two possible fate these conditions,
acetyl-CoA is diverted to the formation of
acetoacetate.
 Ketoacidosis
 • Since acetoacetate and β-hydroxybutyrate are
 moderately strong acids, ↑ levels of these
 ketone bodies ↓ the pH of the bood and cause
 metabolic acidosis.The acidosis caused by over
 production of ketone bodies is termed as ketoacidosis.
Disorders of Ketone Body Metabolism
Ketosis
• Normally the concentration of ketone bodies in blood is very
low (less than 0.2 mmol/L) but in fasting and in diabetes
mellitus it may reach extremely↑
• In addition to β-hydroxybutyrate and acetoacetate, the blood
of diabetics also contains acetone. Acetone is very volatile and
is present in the breath of diabetics, it gives sweet fruity odor.
The overall condition (ketonemia and ketonuria) is called
ketosis.
ALCOHOL METABOLISM
ethanol is a drug. It has high energy content, yielding about
7.1 kcal/g on oxidation. Liver is the major site of ethanol
oxidation. At least 3 enzyme systems
1. Alcohol dehydrogenase (zinc dependent enzyme). principal
pathway for ethanol oxidation. operational for acute
intoxication when the blood alcohol concentration (1–5
mmol/L).
2. Microsomal ethanol oxidizing system (MEOS). MEOS
appears to be a secondary enzyme system for ethanol
clearance. In the chronic alcoholic, ↑ in MEOS activity
3. Catalase of peroxisomes. The role of catalase in biological
oxidation of ethanol is controversial Only 2–10% of ethanol
is excreted unoxidized in the urine and lungs.
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PHOSPHOLIPIDS
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Thank you
DR.Basema