Cholesterol Overview

Cholesterol

• Cholesterol is a major sterol in animal tissues, found in tissues and plasma as free cholesterol or as a storage form, combined with a long-chain fatty acid as cholesteryl ester.
• Cholesterol is transported in lipoproteins.
• Plasma LDL carries cholesterol into tissues.
• Free cholesterol is removed from tissues by plasma high-density lipoprotein and transported to the liver for excretion as bile acids (reverse cholesterol transport).
• Cholesterol is nearly 25% of lipids in plasma membranes of some nerve cells, but may be absent in other intracellular membranes.
• Cells can regulate cholesterol levels by esterifying excess cholesterol with a fatty acid and storing cholesterol esters in vesicles.
• Unesterified cholesterol is transported back to the membrane when needed.
• Cholesterol increases membrane packing, which both alters membrane fluidity and maintains membrane integrity.
• Cholesterol allows animal cells to change shape and for animals to move.
• Cholesterol biosynthesis in hepatocytes is negatively regulated by cholesterol itself, primarily influencing the HMG-CoA reductase reaction.

SREBPs

• SREBPs (Sterol Regulatory Element Binding Proteins) activate the cholesterol and fatty acid synthesis program in the liver.
• Different SREBPs (SREBP-1c and SREBP-2) preferentially activate genes related to cholesterol and/or fatty acid and triglyceride metabolism.
• In the presence of cholesterol or oxysterols, SREBP-Scap is retained in the ER.
• In the absence of sterols, SREBP-Scap is loaded into COPII vesicles through interactions with Sec23/24
• After transport to the Golgi, SREBP's transcription factor domain is released from the membrane by proteolytic cleavage events (S1P and S2P proteases).

HMG-CoA Reductase (HMGCR)

• HMG-CoA reductase is the rate-limiting step in cholesterol synthesis in hepatocytes.
• The enzyme is competitively suppressed under normal conditions due to negative feedback regulation by end products like cholesterol and oxysterols.
• It plays a crucial role in regulating cholesterol biosynthesis from acetyl-CoA to mevalonate.
• HMG-CoA reductase is a target of statins, a class of pharmaceuticals used to reduce cholesterol levels.

Mevalonate Pathway

• The mevalonate pathway is also known as the isoprenoid pathway or HMG-CoA reductase pathway and is present in eukaryotes, archaea, and some bacteria.
• The pathway produces isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP).
• These building blocks are used to produce isoprenoids, a diverse class of biomolecules, such as cholesterol, vitamin K, coenzyme Q10, and steroid hormones.

Cholesterol Absorption and Excretion

• Cholesterol in the intestine must be incorporated into micelles for absorption in the enterocyte.
• Cholesterol is absorbed through NPC1L1 (Niemann-Pick C1-like 1)
• Cholesterol esters are hydrolyzed and become free cholesterol to be incorporate into the micelles.
• Phytosterols, transported via ABCG5/ABCG8, are also absorbed but can displace cholesterol.
• Cholesterol not absorbed is excreted in feces.
• Fecal excretion, with no cholesterol oxidative pathways in humans, is the primary route for cholesterol catabolism.
• Ezetimibe blocks cholesterol absorption by inhibiting NPC1L1.

Familial Hypercholesterolemia (FH)

• FH is a genetic disorder characterized by elevated LDL-C levels.
• In most cases (75%), it is due to mutations in the LDLR gene, leading to defective LDL receptor function.
• Elevated LDL levels can cause early atherosclerosis.
• Homozygous FH (two mutated alleles) is a serious form with very high LDL that presents with severe clinical manifestations and generally requires aggressive management.
• Heterozygous FH(one mutated allele) is less severe.

This quiz explores the role and function of cholesterol in animal tissues, including its transport, regulation, and impact on cell membranes. Learn about the different lipoproteins and the importance of cholesterol in maintaining membrane integrity. Test your knowledge on how cholesterol contributes to cellular shape and animal movement.