Cholesterol Metabolism

By

Amr S. Moustafa, M.D.; Ph.D.

Outlines Overview and Functions

Liver cholesterol pool

Structure and Types

Synthesis and Regulation

Bile acids and salts

Enterohepatic circulation

Overview and Functions

Major Sterol of animal tissues Component of cell membranes Precursor for:

Bile acids & saltsVitamin D Steroid hormones:

Mineralocorticoids e.g., AldosteroneGlucocorticoids, e.g., CortisolSex hormones, e.g., Testosterone

Estrogen & progesterone Hypercholesterolemia: Atherosclerosis & CAD

Liver Cholesterol Pool

Cholesterol:

Structure

Cholesterol: Types

Animal sterol: Cholesterol

Plant sterol: β-Sitosterol Poor intestinal absorption Active transport to intestinal lumen Block cholesterol absorption Dietary treatment of hypercholesterolemia (Trans fatty acid-free margarine)

Animal and plant sterols:

Cholesterol: Types

Free cholesterol Esterified cholesterol

OH at C3HydrophobicMembranesCellsPlasmaTransportBile

FreeLessFoundVariableLessLDL/HDLPresent (PL & bile salts)

Fatty acidMoreAbsentLow levelsMostHDL/LDLAbsent

CONT’D

Cholesterol: Synthesis

All tissues, e.g., Liver, Intestine, Adrenal cortex, & Reproductive organs

Cytosol & ER Building blocks: Acetyl CoA Reducing equivalents: NADPH

Thioester bond &ATP Rate-limiting enzyme: HMG CoA reductase

CONT’D

Cholesterol: Synthesis CONT’D

CONT’D

Cholesterol: Synthesis CONT’D

Internsic ER membrane

Catalytic domain, cytosol

Regulation of Cholesterol Synthesis

Sterol-dependent: Cholesterol contentSREBPStability of mRNA & HMG CoA protein

Hormonal-dependent: Insulin (+), Glucagon (-)

(A) HMG CoA gene expression:

(B) Phosphorylation/dephosphorylation: Sterol-independent, Hormonal-dependent Dephospho-form: Active

(C) Statin drugs: Reversible, competitive inhibitors

Regulation of Cholesterol Synthesis CONT’D

Cholesterol: Degradation

Cholesterol secretion into bile:CholesterolCoprostanolCholeastanol

Reduced productsBacteria

Neutral fecal sterols

Intact sterol nucleus: Bile acids & salts

Bile Acids and Salts

Primary bile acids:Cholic acid and Chenodeoxycholic acid

Bile acids:24 C, 2 or 3 OH-COOH at side chainAmphipathic, Emulsifying agents

Bile salts (Conjugated bile acids):amide-linked with glycine or taurine

GlycocholicTaurocholic

GlycochenodeoxycholicTaurochenodeoxycholic

Bile Acids: Synthesis

Bile Salts

More effective detergent

-COOH (glycine) & -SO4 (taurine): Fully-ionized

Only bile salts, but not acids, found in bile Important for cholesterol excretion:

metabolic productsSolubilizer for cholesterol in bile

Genetic deficiency: Exogenous bile acids

Secondary Bile Acids

Bile salts Glyco- or Tauro-cholic -Chenodeoxycholic

Bile acids Cholic acid Chenodeoxycholic

2° Bile acids Deoxycholic acid Lithocholic

Intestinal bacteria

Intestinal bacteria

GlycineTaurine

OH

Enterohepatic Circulation

CholelithiasisCauses:

bile salts in bile:malabsorption syndromeBiliary tract obstructionhepatic dysfunction

Biliary cholesterol excretion

Treatment: Bile acid replacement therapy Surgical

Hypercholesterolemia

Cholesterol blood level:Familial Hypothyroidism Diabetes mellitusNephrotic syndrome Obstructive jaundice

Treatment: Dietetic Bile acid sequestrants, e.g., Cholestyramine Statin drugs