Cholesterol Metabolism Overview

Cholesterol Metabolism

• Cholesterol is a crucial animal steroid, maintaining membrane fluidity and insulating nerve fibers.
• It's the precursor for bile acids/bile salts, steroid hormones, and vitamin D₃.
• The liver plays a central role in cholesterol homeostasis.
• Major sources of liver cholesterol include dietary cholesterol, chylomicron remnants, de novo synthesis in the liver, cholesterol synthesized in extrahepatic tissues, and HDL.
• Liver cholesterol pool, secretion of VLDL, and conversion to bile acids/salts are key routes by which cholesterol leaves the liver.
• Cholesterol's structure includes a hydrocarbon tail and a steroid nucleus.
• Cholesteryl esters (CEs) are the esterified form of cholesterol with a fatty acid, and these are not found in cell membranes.
• CEs are more hydrophobic than cholesterol and are found in small amounts in most cells.
• Cholesterol synthesis occurs in all tissues, with major sites including the liver, adrenal cortex, testes, ovaries, and intestine.
• All carbon atoms in cholesterol come from acetyl CoA.
• Enzymes for cholesterol biosynthesis are partly located in the endoplasmic reticulum (ER) and partly in the cytoplasm.

Synthesis of HMG-CoA

• HMG-CoA is present in both cytosol and mitochondria, involved in both cholesterol synthesis and mitochondrial ketogenesis.
• Two acetyl CoA molecules combine to form HMG-CoA.

Synthesis of Mevalonic Acid

• Mevalonic acid synthesis is a rate-limiting and key step in the cytosol.
• HMG-CoA reductase, an ER membrane enzyme with a cytosolic catalytic unit, is crucial for this step.
• The process involves the reduction of HMG-CoA to mevalonic acid, requiring NADPH.

Further Steps in Cholesterol Synthesis

• Phosphorylation of mevalonate and the presence of pyrophosphate keeps the water-insoluble compounds in solution.
• Intermediate steps in cholesterol biosynthesis involve non-phosphorylated, hydrophobic compounds.
• These compounds require an intracellular sterol carrier protein for solubility.
• The steps follow specific sequences through intermediates like isopentenyl pyrophosphate (IPP), farnesyl pyrophosphate (FPP), geranyl pyrophosphate (GPP), and 3-dimethylallyl pyrophosphate (DPP).
• Squalene synthesis, squalene monooxygenase, lanosterol formation, and finally, cholesterol are part of the process.

Regulation of Cholesterol Synthesis

• HMG-CoA reductase is the rate-limiting enzyme in cholesterol synthesis.
• The regulation of HMG-CoA reductase involves sterol-dependent regulation of gene expression, sterol-independent phosphorylation/dephosphorylation, and hormonal regulation.

Sterol-Dependent Regulation of HMG-CoA Gene Expression

• Sufficient cholesterol presence results in suppressed transcription.
• Sterol regulatory element (SRE) is a recognition sequence in the DNA for SREBP (sterol regulatory element binding protein).
• SREBP binding is critical for HMG-CoA reductase gene transcription.
• SREBP cleavage-activating protein (SCAP) is an intracellular cholesterol sensor.

Enzyme Phosphorylation/Dephosphorylation

• AMP-activated protein kinase (AMPK) phosphorylates HMG-CoA reductase, making it inactive.
• Dephosphorylation reactivates the enzyme.
• High AMP levels correlate with decreased cholesterol synthesis.

Hormonal Regulation

• Insulin and thyroxine increase HMG-CoA reductase expression.
• Glucagon and cortisol have the opposite effect.

Excretion of Cholesterol

• Cholesterol is excreted via conversion to bile acids and bile salts in the feces.
• Cholesterol is secreted in bile, then transported to the intestine for elimination.
• Intestinal bacteria convert some cholesterol to coprostanol and cholestanol.

Hypercholesterolemia

• High cholesterol concentration in the blood leads to atherosclerosis.
• Statins, structural analogs of HMG-CoA reductase, are drugs used to reduce plasma cholesterol.
• Statins inhibit HMG-CoA reductase activity through competitive inhibition.

β-Sitosterols/Phytosterols

• Plant sterols are poorly absorbed by humans.
• They block the absorption of dietary cholesterol.
• β-Sitosterols/Phytosterols are useful in dietary treatments for hypercholesterolemia.

Bile Acids

• Cholesterol is oxidized in the liver to form various bile acids.
• Bile acids are conjugated with glycine, taurine, or glucuronic acid.
• A mixture of conjugated and non-conjugated bile acids, along with cholesterol, is released into the bile.
• Most bile acids are reabsorbed from the intestine, with a small amount lost in the feces.

Bile Salt Deficiency: Cholelithiasis

• Cholelithiasis is the precipitation of cholesterol in the gallbladder, causing gallstones.
• This can happen due to decreased bile acids in the bile or increased biliary cholesterol excretion (as seen with some drugs).

7-α-Hydroxy Cholesterol

• 7-α-hydroxylase is a key enzyme in bile acid synthesis.
• Converts cholesterol to 7-hydroxy cholesterol, which is further processed.

This quiz covers the essential aspects of cholesterol metabolism, highlighting its role in maintaining cellular functions and its synthesis in the liver. Key processes such as cholesterol homeostasis, the formation of bile acids, and the structure of cholesteryl esters are discussed. Test your knowledge on the crucial functions and pathways of cholesterol in the body.