What is cholesterol metabolism?

Cholesterol Metabolism: A Comprehensive Overview

Cholesterol is a vital molecule in the human body that serves multiple essential functions including cell membrane structure, hormone synthesis, and bile acid production, with its metabolism involving complex pathways of synthesis, transport, and elimination that directly impact cardiovascular health and overall mortality. 1

Cholesterol Sources and Synthesis

• Endogenous synthesis: Approximately 70% of cholesterol is synthesized in the body, primarily in the liver and intestines 2
• Exogenous sources: Dietary cholesterol accounts for about 30% of the body's cholesterol pool 2
• Synthesis regulation: The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the key regulatory enzyme in cholesterol biosynthesis 3
• Feedback control: Intracellular cholesterol levels regulate synthesis through sterol regulatory element binding proteins (SREBPs) 4

Lipoprotein Transport System

Cholesterol is transported in the bloodstream by lipoproteins, which include:

1. Chylomicrons:

   • Formed in intestinal cells from dietary fats and cholesterol
   • Transport dietary lipids to peripheral tissues and liver 4
   • Broken down by lipoprotein lipase (LPL) into chylomicron remnants 4

2. Very Low-Density Lipoproteins (VLDL):

   • Assembled in the liver's endoplasmic reticulum
   • Primary carriers of triglycerides but also contain cholesterol
   • Contain apolipoprotein B100 and phospholipids on their surface 4, 1

3. Intermediate-Density Lipoproteins (IDL):

   • Formed during VLDL metabolism
   • Some are removed by the liver, others converted to LDL 4, 1

4. Low-Density Lipoproteins (LDL):

   • Main carriers of cholesterol in plasma
   • Deliver cholesterol to peripheral tissues via LDL receptors
   • Apolipoprotein B100 is the main surface protein 4, 5
   • Small, dense LDL particles are more susceptible to oxidation and more atherogenic 4

5. High-Density Lipoproteins (HDL):

   • Transport cholesterol from peripheral tissues to the liver ("reverse cholesterol transport")
   • Considered protective against cardiovascular disease 4, 1
   • HDL functionality includes cholesterol efflux capacity 4

Regulatory Mechanisms

• SREBP pathway: When intracellular cholesterol is low, SREBPs activate genes for cholesterol synthesis and LDL receptor expression; when high, this pathway is suppressed 4
• LDL receptor regulation: Controls uptake of LDL particles from circulation; defects in these receptors cause familial hypercholesterolemia 4
• Cholesterol esterification: Free cholesterol is esterified by ACAT2 in enterocytes and stored as cholesterol esters 1
• Bile acid conversion: Primary mechanism for cholesterol elimination from the body 1, 5

Cholesterol Absorption and Intestinal Processing

• Absorption mechanism: Free cholesterol is incorporated into mixed micelles in the intestinal lumen and absorbed via NPC1L1 protein transporters 1
• Esterification: After absorption, cholesterol is re-esterified by ACAT2 within enterocytes 1
• Chylomicron formation: Esterified cholesterol is packaged into chylomicrons with triglycerides and secreted into the lymphatic system 1

Cholesterol Elimination

• Bile acid conversion: The liver converts cholesterol to bile acids, which are secreted into bile 5
• Direct biliary secretion: Free cholesterol can be directly secreted into bile 6
• Transintestinal cholesterol excretion: An additional pathway for cholesterol elimination directly through the intestine 4, 6

Pathological Implications

• Dyslipidemia: Characterized by elevated LDL-C, reduced HDL-C, and increased triglycerides 4
• Atherosclerosis: Results from cholesterol accumulation in arterial walls, particularly from small, dense LDL particles 4, 6
• Genetic disorders: Familial hypercholesterolemia results from LDL receptor defects, causing severely elevated LDL-C levels 4
• Lipotoxicity: Occurs when lipids accumulate in non-adipose tissues, causing cellular dysfunction 4

Pharmacological Interventions

• Statins: Inhibit HMGR, reducing cholesterol synthesis; rosuvastatin reduces LDL-C by 22-30% in various populations 7
• Fibrates: Activate PPARα, increasing lipolysis and elimination of triglyceride-rich particles while altering LDL composition from small dense particles to larger, less atherogenic ones 8
• Bile acid sequestrants: Promote cholesterol excretion by preventing bile acid reabsorption 1
• Plant sterols/stanols: Displace cholesterol from micelles, reducing absorption 1

Clinical Considerations

• Ratio importance: The ratio of total cholesterol to HDL-C is a better indicator of heart disease risk than LDL-C alone 4
• Particle size matters: Small, dense LDL particles are more atherogenic than larger LDL particles 4
• Individual variation: Genetic polymorphisms cause wide variations in individual responses to dietary cholesterol 4
• Metabolic syndrome: Often features an atherogenic dyslipidemia pattern with elevated triglycerides, low HDL-C, and small, dense LDL particles 4

Understanding cholesterol metabolism is essential for managing cardiovascular risk and developing effective therapeutic strategies for dyslipidemia and related disorders.