CHOLESTEROL METABOLISM

STRUCTURE OF CHOLESTEROL

CHOLESTEROL-STRUCTURE

CHOLESTEROL-STRUCTURE

• Steroid alcohol

• Steroid nucleus with 4 fused rings + 8C branched chain attached to C 17

• Ring A has alcohol at C3

• Ring B has a double bond between C5=C6

FUNCTIONS

• Cholesterol performs these main functions:

1. It helps make the outer coating of cells (membrane) and keeps it fluid. Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction.

2. In many neurons, a myelin sheath, rich in cholesterol provides insulation for more efficient conduction of impulses.

3. It makes up the bile acids that work to digest food in the intestine.

4. It allows the body to make Vitamin D

5. It allows the body to make steroid hormones, like estrogen in women and testosterone in men.

HIGH CHOLESTEROL FOOD

CHOLESTEROL METABOLISM

CHOLESTEROL METABOLISM

CHOLESTEROL LEVEL IN BLOOD

• Normal = 150-200 mg%

• Hypercholesterolemia:-

Diabetes Mellitus (↑Lipolysis→↑FFA →↑β Oxid →↑AcetylCoA)

Hypothyroidism (↓LDL Receptor→ ↓ LDL Clearance)

Obstructive Jaundice (↓ excretion)

Nephrotic Syndrome (↑Apo B 100 →↑VLDL →↑LDL →↑Cholesterol)

Primary HyperLipoproteinemia Type II (↓ Receptor)

Smoking

Alcohol intoxication (↑NADH/NAD ratio → ↓TCA →↑Acetyl CoA)

CHOLESTEROL LEVEL IN BLOOD

LDL cholesterol Optimal: less than 100 mg/dL Near-optimal: 100 to 129 mg/dL Borderline high: 130 to 159 mg/dL High: 160 to 189 mg/dL Very high: 190 mg/dL and above. Guidance is also set out for the other measures in the lipid profile:6 Total cholesterol Desirable: less than 200 mg/dL Borderline high: between 200-239 mg/dL High: 240 mg/dL or above. HDL cholesterol Low: below 40 mg/dL High: 60 mg/dL or above.

ATHEROSCLEROSIS • ↑Plasma Cholesterol

→deposition of Cholesterol in the endothelial lining of blood vessels

→plaque

→Atherosclerosis

→Narrowing of blood vessels

→ ↑risk of Cardiovascular / Cerebrovascular

/ Peripheral vascular diseases

→Life threatening

CHOLESTEROL HOMEOSTASIS

• Cholesterol pool in liver

• Source:-

(a) Diet

(b) De Novo synthesis in Liver

(c) De Novo synthesis in all extrahepatic tissues :-specially adrenal cortex, reproductive tissue, (ovaries,testes,placenta), intestine

• Elimination:-

(a) Cholesterol in bile

(b) Bile salts

(c) Plasma lipoproteins (VLDL) → peripheral tissue

CHOLESTEROL SYNTHESIS

CHOLESTEROL SYNTHESIS

• Takes place in all tissues

• Specially important:- liver, Adrenal cortex,Ovaries, Testes, Placenta, Intestine

CHOLESTEROL SYNTHESIS REQUIREMENTS

• Acetate→ All C atoms

• NADPH → Reducing equivalents

• ATP →ADP + Pi + energy

• Acetyl CoA→ hydrolysis of high energy thioester bonds → energy

• Enzymes in cytosol and membrane of SER

• Regulatory mechanisms to balance

Rate of synthesis: Rate of excretion

1. SYNTHESIS OF HMG CoA

• 2 Acetyl CoA condense → Acetoacetyl CoA

• Acetyl CoA + Acetoacetyl CoA → HMG CoA(6C)

• Enzyme = HMG CoA Synthase

2 isoenzymes:-

(a) Cytosolic → Cholesterol synthesis

(b) Mitochondrial → Ketone body synthesis

SYNTHESIS OF HMG CoA

2. SYNTHESIS OF MEVALONATE • HMG CoA (reduced) → 6 C Mevalonate

• HMG CoA Reductase (ER membrane protein with catalytic domain in cytosol)

• It is the rate limiting and regulated step

• 2 NADPH = reducing agent

• Releases CoA (action becomes irreversible)

SYNTHESIS OF 6 C MEVALONATE

HMG CoA REDUCTASE

3. SYNTHESIS OF SQUALENE

a. Mevalonate + ATP → + ATP → 5-pyrophosphate mevalonate

• Enzyme= Kinase

SYNTHESIS OF SQUALENE

b. 5-pyrophosphomevalonate is decarboxylated →Isopentenyl pyrophosphate (IPP) 5 C

(an isoprenoid)

• Enzyme= Decarboxylase

SYNTHESIS OF SQUALENE

c. IPP isomerized → 5 C

DPP

(Dimethylallyl

Pyrophosphate)

• Enzyme = Isomerase

SYNTHESIS OF SQUALENE

d. IPP + DPP condense → 10 C GPP

(Geranyl pyrophosphate )

• Enzyme = Transferase

SYNTHESIS OF SQUALENE

e. IPP + GPP → FPP

( 15 C Farnesyl pyrophosphate)

• Enzyme = Transferase

SYNTHESIS OF SQUALENE

f. 2 FPP condense and reduce → PPi + SQUALENE (30 C)

• 6 IPP required

• 18 ATP required ( 3 ATP/ Mevalonate →IPP)

• Enzyme = Squalene synthase

SYNTHESIS OF SQUALENE

SYNTHESIS OF LANOSTEROL • Squalene is hydroxylated

→cyclization →Lanosterol

• ER associated enzymes

• O2, NADPH needed

SYNTHESIS OF CHOLESTEROL

• Many enzymes involved

• ER associated pathway

a)30 C chain→ 27 C

b)2 Methyl groups at C 4 removed

c)Double bond migrates from C8→C5

d)Double bond between C24 and 25 reduced

→ Cholesterol

SYNTHESIS OF CHOLESTEROL

REGULATION OF CHOLESTEROL SYNTHESIS

(HMG CoA REDUCTASE) 1. Sterol levels in cell control gene expression

2. Sterols reduce enzyme activity

3. AMPK(AMP activated protein kinase) inactivates the enzyme by phosphorylation.

Phosphatase activates it by dephosphorylation

(↑ATP→↑Cholesterol synthesis)

4. Insulin/Thyroxine→↑HMG CoA reductase gene

Glucagon/Glucocorticoids→↓gene

5. Statin drugs→structural analogs of HMG CoA

→Competitive inhibitors of HMG CoA reductase

→used to ↓plasma Cholesterol level

DEGRADATION OF CHOLESTEROL

• Cholesterol ring cannot be opened

• Intact sterol nucleus →eliminated in feces as

(a) Bile acids and Bile salts

(b) Cholesterol→reduced by intestinal bacteria →Coprostanol and Cholestanol

DEGRADATION OF CHOLESTEROL

BILE ACIDS AND BILE SALTS

• Bile = Dilute solution of Cholesterol,

Bile salts + Lecithin (Phosphatidyl choline)

• Synthesized in liver → Common Bile duct

→stored in Gall bladder

→secreted into duodenum

BILE ACIDS

• 24 C

• 2-3 OH groups

• Side chain ends at Carboxyl group (i.e. acids)

• Amphipathic because of OH group and methyl group→polar and non polar faces

( Oh groups lie below plane of ring and CH3 groups above the plane of ring)

→emulsifying agents in intestine

→ prepare lipids for hydrolytic enzymes

BILE ACIDS

SYNTHESIS OF BILE ACIDS

• Liver (has enzyme 7αHydroxylase)

• Multistep

• Multiorganelle

• OH groups inserted

• Double bond reduced

• Hydrocarbon chain shortened by 3C

• Carboxyl group added at the end of chain

• →Primary Bile acids ( triol = Cholic acid + diol = ChenodeoxyCholic acid)

SYNTHESIS OF CHOLIC ACID

SYNTHESIS OF BILE SALTS

• In liver →Bile acids → Bile salts

• Bile acids → conjugated with Glycine / Taurine

( derived from Cysteine) →Bile salts

• Carboxyl group of Bile acid forms amide bond with amino group of amino acid

• →Glycocholic / Glycochenodeoxycholic acids

Taurocholic/ Taurochenodeoxycholic acids

• 3 Glycine : 1 Taurine

• Bile salts are more amphipathic (additional acid /SO4

group at the end)

→↑effective detergents than Bile acids

• Mechanism for Cholesterol excretion

BILE SALTS

ACTION OF INTESTINAL FLORA ON BILE SALTS

• Bile salts in intestine

→ Bacteria remove Glycine/ Taurine

→Primary Bile acids

→Remove hydroxyl group from primary Bile acids

→Secondary Bile acids

(Cholic acid→Deoxy Cholic acid

Chenodeoxycholic acid →Lithocholic acid)

ENTEROHEPATIC CIRCULATION • Bile salts secreted in intestine

→95% reabsorbed →reused

→Liver conjugates primary and secondary Bile acids with Glycine/Taurine→Bile→GI

→Bile acids + bile salts absorbed in ileum

(By Na:Bile salt Cotransporter)

(Lithocolic acid is poorly reabsorbed)

→ Portal blood ( carried by Albumin)

→Liver ( mixture of Bile acids and salts)

→ 15-30 gm Bile salts secreted daily

→ 0.5 gm (3%)lost in feces

→0.5 gm synthesized from Cholesterol in liver

TREATMENT OF HYPERCHOLESTEROLEMIA

Cholestyramine/Fiber

→ bind Bile acids in GIT

→prevent reabsorption

→ ↑excretion

→ relieves inhibition of Bile acid synthesis in liver

→ ↑Cholesterol changes to Bile acids

→ ↓ Hypercholesterolemia

Plant sterols

→ ↓ absorption of dietary Cholesterol

(by competition for absorption)

ENTEROHEPATIC CIRCULATION

CHOLELITHIASIS (GALL STONES)

• Cholesterol in Bile must be accompanied with Phopholipids and Bile salts →solubilization

• If ↑Cholesterol →precipitates →Gall stones

(85% of Gall stones- rest are mixed/Bilirubin)

• Causes:-

(a) Ileal disease→malabsorption of Bile acids

(b) Obstruction of Biliary tract→↓enterohepatic circulation

(c) Hepatic dysfunction→↓synthesis of Bile salts

(d) ↓Bile acid synthesis

(e) ↑Biliary Cholesterol

GALL STONES

NORMAL PLASMA CHOLESTEROL • 150-200 mg / dl

CURRENT RECOMMENDATION

HYPERCHOLESTEROLEMIA CAUSES • Environmental + Genetic factors →Hypercholesterolemia • Environmental factors → Obesity/ Dietary choices. • Genetic factors→ additive effects of multiple genes / single gene

defect (e.g. familial hypercholesterolaemia) • Secondary causes:- diabetes mellitus type 2 obesity alcohol dialysis nephrotic syndrome obstructive jaundice Hypothyroidism/ Cushing’s syndrome anorexia nervosa medications (thiazide diuretics, ciclosporin, glucocorticoids, beta

blockers, retinoic acid).

CHOLESTEROL LEVEL IN BLOOD

• Normal = 150-200 mg%

• Hypercholesterolemia:-

Diabetes Mellitus (↑Lipolysis→↑FFA →↑β Oxid →↑AcetylCoA)

Hypothyroidism (↓LDL Receptor→ ↓ LDL Clearance)

Obstructive Jaundice (↓ excretion)

Nephrotic Syndrome (↑Apo B 100 →↑VLDL →↑LDL →↑Cholesterol)

Primary HyperLipoproteinemia Type II (↓ Receptor)

Smoking

Alcohol intoxication (↑NADH/NAD ratio → ↓TCA →↑Acetyl CoA)

HYPERCHOLESTEROLEMIA SIGNS AND SYMPTOMS • Hypercholesterolemia → asymptomatic

• Chronic ↑serum cholesterol→ atherosclerosis.

• Over a period of decades→↑serum cholesterol →atheromatous plaques in the arteries

→ progressive stenosis (narrowing)

/ complete occlusion (blockage) of the involved arteries

• Smaller plaques may rupture→clot→obstructs blood flow

• Sudden occlusion of a coronary artery→myocardial infarction

• Occlusion of an artery supplying the brain→ stroke.

HYPERCHOLESTEROLEMIA SIGNS AND SYMPTOMS • Gradual stenosis/occlusion →slow↓blood supply to the

tissues and organs →↓organ function becomes impaired→ tissue ischemia (restriction in blood supply)→specific symptoms.

• Temporary ischemia of the brain (Transient ischemic attack)→ temporary loss of vision, dizziness and impairment of balance, aphasia (difficulty speaking), paresis (weakness) and paresthesia (numbness or tingling), usually on one side of the body.

• Insufficient blood supply to the heart→ chest pain

• Ischemia of the eye →transient visual loss in one eye.

• Insufficient blood supply to the legs→calf pain when walking,

• Intestinal ischemia→abdominal pain after eating a meal

HYPERCHOLESTEROLEMIA SIGNS AND SYMPTOMS

Some types of hypercholesterolemia lead to specific physical findings.

• Familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids),arcus senilis (white or gray discoloration of the peripheral cornea),and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers.

• Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows

HYPERCHOLESTEROLEMIA CAUSES

HYPERCHOLESTEROLEMIA CAUSES

HYPERCHOLESTEROLEMIA CAUSES

HYPERCHOLESTEROLEMIA CAUSES

HYPERCHOLESTEROLEMIA PATHOPHYSIOLOGY

HYPERCHOLESTEROLEMIA SIGNS AND SYMPTOMS

HYPERCHOLESTEROLEMIA COMPLICATIONS (M.I.)

HYPERCHOLESTEROLEMIA COMPLICATIONS ( STROKE)