Download Cholesterol

Overview of Lipid Metabolism
Learning Objectives
By the end of this lecture the students should be able to understand:
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Classification of Lipids
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The digestion, absorption and utilization of dietary lipids
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Lipogenesis and Lipolysis
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Lipid malabsorption
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The functions of cholesterol
Cholesterol synthesis and metabolism
Cholesterol transport
Classification of lipids
Fatty Acids
•
Fatty acids are long chain carboxylic acids having a terminal carboxyl
(COOH-) group
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Saturated Fatty Acids: have no double bonds e.g. Palmitic acid and
Stearic acid
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Unsaturated Fatty Acids: have one or more double bonds
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Essential Fatty Acids
–
Fatty Acids that can not be synthesized de novo and have to supplied
in the diet
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Linoleic acid
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Linolenic acid
Triglycerides
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When one, two or three fatty acids are esterified to a molecule of
glycerol; they form mono, di or triacylglycerols aka TGs
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Lipids are stored within adipose tissue as fat droplets made up of TGs
Lipogenesis
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Lipid synthesis:
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From glycerol derived from Dihydroxyacetone phosphate from
glycolysis
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Occurs in the liver and to a small extent in adipose tissue
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Acetyl coA can form any fatty acid except for the essential FA
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The main rate limiting enzyme of lipid synthesis is Fatty Acid
Synthase
Lipolysis
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Lipid catabolism where lipids become:
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Glycerol
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Free fatty acids
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Glycerol can be converted to pyruvic acid which enters TCA
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Fatty Acids are degraded by beta oxidation, occurs in mitochondria of
liver, muscle and adipose tissue
The Dietary Lipids
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An adult consumes about 60-150 g of lipid per day
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Much of it is composed of Triglycerides
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Remaining is made up of free Fatty acids, Cholesterol, cholesterol
esters and phospholipids
Digestion of Dietary Lipids
•
Digestion begins in the GIT with the action of Lipase
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Gastric lipase requires neutral pH to emulsify fat
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In adults much of the dietary lipids are transported unchanged to the
small intestine owing to acidic pH of the stomach
Emulsification of Dietary Lipids
•
In the small intestine the pancreatic secretions digest the dietary lipids
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Bile Salts emulsify fat droplets
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Pancreatic lipase digests triglycerides into monoglycerides and free
fatty acids
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Pancreatic cholesterol esterase digests CE into cholesterol and FFA
Absorption of lipids across intestinal mucosa
•
FFA, cholesterol and monoacylglycrol together with bile salts,
constitute micelles to get absorbed across the intestinal mucosal cells
•
Micelles: amphipathic structures with hydrophobic core containing
the water insoluble lipids, and hydrophilic outer shell soluble in aqueous
medium of intestinal epithelium
Lipid transport from intestinal mucosa
•
Once inside the intestinal mucosal cells, the absorbed lipids are
resynthesized into TG and CE ( cholesterol esters )
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Intestinal cells synthesize apolipoprotein B-48 and package TG and
CE into Chylomicrons
•
Chylomicrons are secreted first into the lymphatics and then into the
blood
Lipoproteins
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TGs and Cholesterol are transported in blood as Lipoproteins.
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According to density the lipoproteins are classified as
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Chylomicrons
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VLDL (very low density lipoproteins )
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IDL (intermediate density lipoproteins )
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LDL (low density lipoproteins )
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HDL (high density lipoproteins )
Classes of lipoproteins with associated Apoproteins
Lipoprotein Function
Apoprotein
Chylomicrons
Transport dietary TG and CE from intestine to tissues
apoB-48
apoC-II
apoE
VLDL
Transport TG from liver to tissues
apoB-48
apoC-II
apoE
LDL Delivers cholesterol into cells apoB-100
IDL Picks up cholesterol from HDL to become LDL
Picked up by liver apoE
HDL Picks up cholesterol accumulating in blood vessels apoA1
Lipoproteins and their functions
Complex lipids
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Phospholipids
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Polar, amphipathic, ionic compounds composed of alcohol attached to
a diacylglycerol or sphingosine
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Phosphoglycerides
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Phospholipids containing glycerol
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Sphingomylin
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Phospholipids containing sphingosine
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Fatty acid + sphingosine = Ceramide
Glycolipids
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Derivatives of ceramide
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Components of cell membranes
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Serve as receptors of certain bacterial and viral toxins
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Antigenic: tumor antigens, embryonal antigens and sources of blood
group antigens
Cholesterol
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Component of cell membranes
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Steroid synthesis
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Precursor of steroid hormones e.g. corticosteroids, aldosterone,
estrogen and testosterone
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Vitamin D precursor
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bile acid precursor
Fat malabsorption
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Syndrome of fat malabsorption consists of Diarrhea, steatorria,
malabsorption, wasting and vitamin deficiencies
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Some common causes are:
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Lactase deficiecy
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Celiac sprue
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Pernicious anemia
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Blind loop syndrome
Lymphatic obstruction
Tuberculosis
lymphoma
Deficiencies in Fat malabsorption
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Deficiency of Fat soluble vitamins: vitamin A, D, E and K
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Iron deficiency-Anemia
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Vitamin B12/ Folate deficiency- Megaloblastic anemia
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Vitamin K deficiency- easy bruising
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Vitamin D deficiency- osteopenia
Cholesterol Metabolism and CVS Function
Cholesterol
• The major sterol compose of four fused rings and an eight-membered,
branched hydrocarbon chain
Functions of Cholesterol
• Necessary part of cell membranes
• Precursor molecule for steroid synthesis
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Aldosterone
Corticosteroids
Estrogens
Progesterone
Testosterone
Bile acid for digestion
Vitamin D
Sources of Cholesterol
Cholesterol Synthesis
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Occurs in cytosol
Requires NADPH and ATP
Highly regulated
80 % in liver, ~10% intestine, ~5% skin
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) is the precursor for
cholesterol synthesis.
• HMG-CoA is also an intermediate on the pathway for synthesis of ketone
bodies from acetyl-CoA.
Formation of HMG CoA-Rate Limiting step
 HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-
CoA, catalyzed by HMG-CoA Synthase.
 HMG-CoA Reductase catalyzes production of mevalonate from HMGCoA
O
H3 C
H2 O  O
H3 C
C
CH2
C
SCoA
SCoA
HMG-CoA
Synthase
HSCoA
OH
O
O
C
acetoacetyl-CoA
acetyl-CoA

O
C
CH2
C
O
CH2
C
SCoA
CH3
hydroxymethylglutaryl-CoA
Regulation of Cholesterol Synthesis
Cholesterol Transport
• Chylomicrons:
– Chylomicrons transport triglycerides from intestine
• Very Low Density Lipoproteins (VLDL) and Intermediate Density
Lipoproteins (IDL) :
– VLDL produced in liver . Carry cholesterol and triglycerides
• Low Density Lipoproteins (LDL)
– LDL result from metabolism of VLDL and IDL and carry cholesterol.
LDL are important cause of heart disease
• High Density Lipoproteins(HDL)
– HDL is “good” cholesterol. It removes cholesterol and protects against
heart disease
Cholesterol
Transport
Hypercholestrolemia
Blood Cholesterol levels
• Total cholesterol
< 5.17 mmol/L = Good
5.17-6.19
= Borderline High
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> 6.20
= High
LDL
< 2.58 mmol/L = Good
2.58-3.33 = Near Normal
3.34- 4.12 = Borderline High
4.13-4.88 = High
> 4.88
= Very High
Hypercholestrolemia
Hypercholestrolemia-Risk factor for
Atherosclerosis
Atherosclerosis
Hypercholesterolemia and Risk of Stroke
HDL-Cardio protective Lipoprotein
Management of Hypercholestrolemia
• Life style modifications
– Balanced diet
– Exercise
– Stress management
• Drug Therapy
REFERENCE
Lippincott’s Illustrated Review
Biochemistry
5th Edition
Page no. 219 to 224
THANKS