What is the fatty substance produced by the liver that travels through the bloodstream?

Cholesterol: The Fatty Substance Produced by the Liver

Cholesterol is the primary fatty substance produced by the liver that travels through the bloodstream, transported by lipoproteins including VLDL, LDL, and HDL, each serving distinct roles in lipid metabolism. 1

Hepatic Cholesterol Production and Transport

Cholesterol is synthesized in the liver from acetate and then packaged into lipoproteins for transport through the bloodstream. The liver is considered the metabolic "power station" of the body, where cholesterol homeostasis is maintained through several processes 2:

• Biosynthesis: Occurs via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity
• Packaging: Cholesterol is incorporated into lipoproteins for transport
• Transport: Primarily carried by different lipoprotein particles

Lipoprotein Transport System

The liver produces and secretes very low-density lipoproteins (VLDL), which are assembled in the endoplasmic reticulum of hepatocytes 3. These particles contain:

• Triglycerides (primary component)
• Cholesterol (synthesized in the liver or delivered by other lipoproteins)
• Apolipoprotein B100 and phospholipids (surface components)

Once in circulation, VLDL undergoes the following transformation:

1. VLDL triglyceride is hydrolyzed by lipoprotein lipase (LPL)
2. This generates smaller, denser VLDL and subsequently intermediate-density lipoprotein (IDL)
3. IDL particles can be removed by the liver or further metabolized to low-density lipoprotein (LDL) 3

Cholesterol Transport Pathways

Forward Cholesterol Transport

• LDL particles are the main carriers of cholesterol in plasma (70-80% of circulating cholesterol)
• LDL delivers cholesterol to peripheral tissues via LDL receptors
• Apolipoprotein B100 is the main surface protein on LDL 1
• The lifetime of LDL in plasma is determined mainly by the availability of LDL receptors 3

Reverse Cholesterol Transport

• HDL particles transport cholesterol from peripheral tissues back to the liver
• This process is considered protective against cardiovascular disease
• HDL functionality includes cholesterol efflux capacity 1
• HDL is the only pathway for removing excess cholesterol from peripheral tissues 4

Clinical Implications

Disruptions in cholesterol metabolism can lead to several pathological conditions:

• Hypercholesterolemia: Elevated levels of cholesterol in the blood, often due to increased LDL
• Atherosclerosis: Results from cholesterol accumulation in arterial walls, particularly from small, dense LDL particles 1
• Metabolic-associated fatty liver disease: Characterized by pathological accumulation of lipids in hepatocytes 5

Risk Assessment

• The ratio of total cholesterol to HDL-C is considered a better indicator of heart disease risk than LDL-C alone 1
• Small, dense LDL particles are more susceptible to oxidation and are more atherogenic than larger LDL particles 3

Regulation of Cholesterol Metabolism

Cholesterol homeostasis is maintained through a complex regulatory system:

• SREBP pathway: Controls cholesterol synthesis and LDL receptor expression based on intracellular cholesterol levels 1
• LDL receptor regulation: Controls uptake of LDL particles from circulation 1
• Bile acid production: The liver converts cholesterol to bile acids for excretion 6

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