Lecture Lipid 3

Cholesterol Overview

  • Types of Cholesterol:

    • Free cholesterol

    • Cholesterol esters

  • Characteristics of Cholesterol:

    • Amphipathic lipid, essential for cell membranes

  • Precursor Roles:

    • Precursor for steroid hormones (adrenal cortex, gonads)

    • Precursor for bile acids (produced by the liver)

    • Precursor for Vitamin D3 (produced in the skin)

  • Sources of Cholesterol:

    • Exogenous:

      • Dietary intake (animal-based foods)

    • Endogenous:

      • Synthesis within the body

Biosynthesis of Cholesterol

  • Location:

    • Primarily in liver, small intestine, adrenal cortex, and gonads

  • Synthesis Process:

    • Derived from acetyl-CoA

    • Requires NADPH (reducing power) and ATP (energy investment)

    • Occurs in the cytosol and endoplasmic reticulum

Key Steps in Cholesterol Biosynthesis:

  1. Formation of mevalonate from acetyl-CoA

  2. Conversion of mevalonate to activated isoprenes

  3. Formation of squalene from six activated isoprenes

  4. Conversion of squalene to cholesterol

Detailed Steps

Synthesis of Mevalonate

  • Three acetyl-CoA molecules condense to form HMG-CoA

  • Reactions are similar to ketone body synthesis, albeit occurring in liver mitochondria

Reactions Involving HMG-CoA

  • Reduction:

    • HMG-CoA is reduced to mevalonate via HMG-CoA reductase; reaction consumes NADPH

Phosphorylation of Mevalonate

  • Three ATPs contribute phosphate groups to mevalonate, preparing it for further reactions

Isoprene Units Formation

  • Head-to-tail condensation of isoprenoid units leads to the formation of geranyl-PP (10C) and farnesyl-PP (15C) from dimethylallyl pyrophosphate

Formation of Squalene

  • Two molecules of farnesyl-PP undergo fusion, forming squalene (30C)

Conversion of Squalene to Cholesterol

  • Monooxygenase Action:

    • Adds oxygen to squalene, creating an epoxide intermediate

  • Transformation of squalene epoxide into lanosterol, followed by conversion into cholesterol

Regulation of Cholesterol Biosynthesis

  • Key Enzyme: HMG-CoA reductase is rate-limiting

  • Mechanisms of Regulation:

    • Transcriptional control by SREBP (sterol regulatory element binding proteins)

    • Covalent regulation (phosphorylation and dephosphorylation)

SREBP Mechanism

  • SREBP activity increases mRNA synthesis for HMG-CoA reductase

  • Inhibition occurs when cholesterol levels rise, reducing transcriptional activity

Hormonal Control

  • Insulin and thyroid hormones enhance gene expression for HMG-CoA reductase

  • Glucagon and glucocorticoids decrease expression of the gene

Phosphorylation Effects

  • HMG-CoA reductase inactivation occurs via phosphorylation by AMP-activated protein kinase (AMPK), sensing low energy levels

Statin Drugs

  • Function: Competitive inhibitors of HMG-CoA reductase

  • Purpose: Used to lower plasma cholesterol in cases of hypercholesterolemia

Bile Acid Synthesis from Cholesterol

  • Process: Occurs in liver cells, cholesterol is converted into bile acids

    • Involves 7 α-hydroxylase (rate-limiting step)

  • Types of Primary Bile Acids:

    • Cholic acid and chenodeoxycholic acid

Conjugation and Action of Bile Salts

  • Bile acids conjugated with glycine or taurine

  • Function: Facilitate lipid digestion by emulsifying fats and increasing surface area

Recycling of Bile Salts

  • Recycling occurs through entero-hepatic circulation

  • 5-6 cycles daily, with a minimal fraction excreted daily in feces

References

  • Nelson, D. L. et al. (2008). Lehninger Principles of Biochemistry. 5th edition.

  • Smith, C. et al. (2004). Marks’ Basic Medical Biochemistry: A Clinical Approach. 2nd edition.

  • Murray, R. K. et al. (2006). Harper’s Illustrated Biochemistry. 27th edition.

  • Champe, P. C. et al. (2007). Lippincott’s Illustrated Reviews: Biochemistry. 4th edition.

  • Garrett, R. H. et al. (1999). Biochemistry. 2nd edition.

  • Campbell, M. K. et al. (2007). Biochemistry. 6th edition.