View
218
Download
2
Category
Preview:
Citation preview
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
Recommended