3.4 Cholesterol metabolism and regulation

Cholesterol metabolism is a complex process that impacts our health in big ways. From its synthesis in our cells to its transport through our blood, cholesterol plays a crucial role in our bodies.

Understanding how cholesterol is made, moved, and regulated helps us grasp why it's so important for our health. It also sheds light on how we can manage cholesterol levels to prevent heart disease and other health issues.

Cholesterol Biosynthesis

Synthesis Pathway and Key Enzymes

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• Cholesterol biosynthesis occurs in the endoplasmic reticulum and cytosol of cells, primarily in the liver
• Process begins with acetyl-CoA, which undergoes condensation to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
• HMG-CoA reductase catalyzes the rate-limiting step, converting HMG-CoA to mevalonate
  • Primary target for regulation of cholesterol biosynthesis
• Mevalonate converts through multiple steps to farnesyl pyrophosphate
• Squalene synthase forms squalene from farnesyl pyrophosphate
• Squalene undergoes cyclization and a series of oxidation and reduction reactions to form lanosterol
• Lanosterol converts to cholesterol through several additional steps
  • Involves enzymes such as lanosterol 14α-demethylase and 7-dehydrocholesterol reductase

Regulation of Cholesterol Synthesis

• Feedback inhibition regulates cholesterol biosynthesis
  • High cholesterol levels suppress HMG-CoA reductase activity and expression
• Sterol regulatory element-binding proteins (SREBPs) mediate transcriptional regulation
  • Respond to cellular sterol levels
  • Control expression of genes involved in cholesterol synthesis (HMG-CoA synthase, HMG-CoA reductase)
• Post-translational regulation occurs through protein degradation
  • Excess cholesterol promotes degradation of HMG-CoA reductase
• Hormonal regulation influences cholesterol synthesis
  • Insulin stimulates cholesterol synthesis
  • Glucagon inhibits cholesterol synthesis

Lipoprotein Transport and Homeostasis

Lipoprotein Structure and Classification

• Lipoproteins consist of a hydrophobic core containing cholesterol esters and triglycerides
  • Surrounded by a hydrophilic shell of phospholipids, free cholesterol, and apolipoproteins
• Major classes of lipoproteins involved in cholesterol transport
  • Chylomicrons (transport dietary cholesterol from intestine to peripheral tissues and liver)
  • Very-low-density lipoproteins (VLDL)
  • Low-density lipoproteins (LDL, "bad cholesterol")
  • High-density lipoproteins (HDL, "good cholesterol")
• Apolipoproteins on lipoprotein surfaces play crucial roles in metabolism
  • Act as cofactors for enzymes (apoC-II activates lipoprotein lipase)
  • Serve as ligands for cell-surface receptors (apoB-100 binds to LDL receptor)

Lipoprotein Metabolism and Cholesterol Transport

• VLDL and LDL primarily transport endogenous cholesterol from liver to peripheral tissues
  • LDL serves as the main carrier of cholesterol in the blood
• HDL facilitates reverse cholesterol transport
  • Moves excess cholesterol from peripheral tissues back to liver for excretion or recycling
• LDL receptor pathway enables cellular uptake of cholesterol-rich LDL particles
  • Maintains cholesterol homeostasis in cells and tissues
  • Genetic defects in LDL receptor lead to familial hypercholesterolemia
• Cholesteryl ester transfer protein (CETP) mediates exchange of cholesteryl esters between HDL and other lipoproteins
  • Influences HDL cholesterol levels and reverse cholesterol transport efficiency

Cholesterol Regulation Mechanisms

Cellular Cholesterol Homeostasis

• Intracellular cholesterol levels sensed by SREBP-SCAP complex in endoplasmic reticulum
  • Controls expression of genes involved in cholesterol synthesis and uptake
• LDL receptor gene upregulation occurs when cellular cholesterol levels are low
  • Increases uptake of LDL particles from bloodstream
• Excess cellular cholesterol undergoes esterification by acyl-CoA:cholesterol acyltransferase (ACAT)
  • Allows for storage or export via ATP-binding cassette (ABC) transporters
• Cholesterol efflux from cells mediated by ABCA1 and ABCG1 transporters
  • Transfer cholesterol to HDL particles for reverse cholesterol transport

Pharmacological Regulation and Therapeutic Approaches

• Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis
  • Effectively lower blood cholesterol levels
  • Lead to increased expression of LDL receptors in the liver
  • Enhance clearance of LDL particles from circulation
• Bile acid sequestrants (cholestyramine, colesevelam) bind bile acids in intestine
  • Promote bile acid excretion and increase cholesterol conversion to bile acids
• PCSK9 inhibitors (evolocumab, alirocumab) prevent LDL receptor degradation
  • Enhance LDL clearance from bloodstream
• Ezetimibe inhibits cholesterol absorption in intestine
  • Reduces dietary and biliary cholesterol uptake

Cholesterol Metabolism and Cardiovascular Disease

Cholesterol and Atherosclerosis

• Elevated LDL cholesterol levels strongly associate with increased atherosclerosis risk
• Atherosclerosis involves accumulation of cholesterol-laden foam cells in arterial walls
  • Leads to plaque formation and potential vessel occlusion
• Low HDL cholesterol levels also associate with increased cardiovascular risk
  • HDL plays a protective role in reverse cholesterol transport
• Oxidized LDL particles contribute to atherosclerosis progression
  • Trigger inflammatory responses in arterial wall
  • Promote foam cell formation

Clinical Management and Risk Assessment

• Familial hypercholesterolemia results from genetic defects in LDL receptor function
  • Causes severely elevated LDL cholesterol levels and premature cardiovascular disease
• Therapeutic interventions for managing cholesterol-related cardiovascular risk include:
  • Lifestyle modifications (diet low in saturated fats, regular exercise)
  • Pharmacological treatments (statins, bile acid sequestrants, PCSK9 inhibitors)
• Blood lipid profile monitoring essential for assessing cardiovascular risk
  • Includes total cholesterol, LDL, HDL, and triglycerides
  • Guides treatment decisions and evaluates therapy effectiveness
• Emerging research focuses on novel targets for cholesterol regulation
  • PCSK9 inhibition
  • Antisense oligonucleotides targeting apolipoprotein B
  • Addresses residual cardiovascular risk in patients not adequately managed by current therapies