L2 Cholesterol Metabolism

A type of lipid with four fused hydrocarbon rings (A-D) called a "steroid nucleus". Contains hydroxyl group at C3, double bond between C5 & C6, eight-membered hydrocarbon chain at C17, & methyl groups at C10 & C13.

Cholesterol plays a crucial role as a membrane component and serves as a precursor for various essential compounds.

Bile acids are steroid derivatives produced by the liver and play a significant role in digestion and absorption of fats.

The process by which bile acids are recycled and reabsorbed in the intestines, contributing to efficient fat digestion.

The synthesis of cholesterol from simpler precursors within cells.

HMG-CoA reductase is an enzyme crucial in cholesterol synthesis and its regulation. Its activity is controlled by various mechanisms.

The balance between the intake and outflow of cholesterol within the body.

Excessive cholesterol deposition in arterial walls leading to narrowing and hardening of blood vessels.

A specific enzyme located in the cytosol, responsible for synthesizing HMG-CoA for cholesterol synthesis. It is distinct from the mitochondrial HMG-CoA synthase used for ketone body formation.

An enzyme located in the endoplasmic reticulum (ER), responsible for converting HMG-CoA to mevalonate, a crucial step in cholesterol synthesis.

A five-carbon isoprenoid formed after phosphorylation and decarboxylation of mevalonic acid. It's a building block for cholesterol synthesis.

A 15-carbon molecule formed from the condensation of five isoprenoid units. Two of these molecules combine to form squalene.

A 30‐carbon molecule crucial in cholesterol synthesis, formed from the joining of two farnesyl pyrophosphate molecules.

A sterol precursor to cholesterol, formed by oxidizing and cyclizing squalene. It undergoes further modifications to become cholesterol.

An enzyme responsible for esterifying cholesterol in the liver. It facilitates cholesterol packaging within VLDL for transport.

A type of gallstone formed due to cholesterol precipitation when bile becomes supersaturated with cholesterol.

Acyl-CoA:cholesterol acyl transferase (ACAT) is an enzyme found in the ER membrane that attaches fatty acids to the C3 hydroxyl group of cholesterol.

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme that esterifies cholesterol associated with HDL in the extracellular space. It contributes to cholesterol transport and metabolism.

The liver is the primary site of cholesterol synthesis, producing around 1 gram per day. Other sites include the intestine, adrenal cortex, ovaries, and testes.

HMG-CoA reductase is a key enzyme in cholesterol synthesis, responsible for converting HMG-CoA to mevalonate. It is the rate-limiting step and is tightly regulated.

The brain is the most cholesterol-rich organ in the body. All of the cholesterol in the brain is synthesized within the central nervous system, particularly important during myelination, the process of forming myelin sheaths around nerve fibers.

The majority of Acetyl-CoA for cholesterol synthesis is generated in the mitochondria and then transported to the cytosol as citrate.

Mevalonate is synthesized from Acetyl-CoA in the cytosol before being transported to the ER for further cholesterol synthesis.

A type of medication that binds to bile acids in the intestine, preventing their reabsorption and reducing LDL by 15-30%. These drugs work by increasing hepatic bile acid synthesis and can cause side effects like GI distress, constipation, and decreased absorption of certain vitamins and drugs.

These medications reduce LDL cholesterol levels by 5-25% by affecting various processes within the body. They increase HDL levels, decrease VLDL synthesis, decrease lipolysis in fat cells, increase lipoprotein lipase activity, and reduce triglycerides in the liver. However, they can cause side effects like flushing, itching, GI distress, hyperglycemia, hyperuricemia, and hepatotoxicity.

These drugs are a class of medications that inhibit HMG-CoA reductase, the enzyme responsible for the synthesis of cholesterol. By lowering cholesterol synthesis, statins effectively reduce LDL cholesterol levels.

Statins work by regulating the transcription of the gene for HMG-CoA reductase.

Plant stanols are plant-derived compounds structurally similar to cholesterol. They differ from cholesterol in that they lack a double bond within their B ring structure. They are often used to reduce cholesterol levels.

Plant sterols are plant-derived compounds with a structure similar to cholesterol. They differ from cholesterol in their side chains.

Lipids, being hydrophobic, need help to be absorbed in the watery environment of the gut. Bile salts, produced by the liver, act as detergents to emulsify lipids, breaking them down into smaller droplets that are easier to absorb.

Bile salts, after helping with lipid absorption, are reabsorbed in the ileum, returning to the liver to be recycled. This efficient process conserves bile salts and ensures a continuous supply for lipid digestion.

HMG-CoA reductase is a key enzyme in the synthesis of cholesterol. Its activity can be regulated at multiple levels, including transcription (gene expression), protein degradation, and covalent modifications.

Glucagon, a hormone released when blood sugar is low, activates phosphorylation of HMG-CoA reductase, leading to its inactivation. This reduces cholesterol synthesis when energy resources are scarce.

Insulin, released when blood sugar is high, promotes dephosphorylation of HMG-CoA reductase, activating it. This increases cholesterol synthesis when energy is abundant.

Statins are drugs that lower cholesterol levels by inhibiting HMG-CoA reductase. They mimic the natural substrate, HMG-CoA, competing for the enzyme's active site and blocking cholesterol synthesis.

By reducing cholesterol synthesis, statins lead to a reduction in intracellular cholesterol levels. This triggers the upregulation of LDL receptors on cells, leading to increased removal of LDL from the bloodstream.

Dietary changes play a crucial role in managing cholesterol levels. Reducing saturated and trans fats, limiting cholesterol intake, and increasing soluble fiber consumption are all important strategies.

Bile acid sequestrants are medications that bind to bile acids in the intestines, preventing their reabsorption and lowering LDL cholesterol levels by 15-30%. They work by increasing bile acid synthesis in the liver.

Niacin (vitamin B3) in high doses can reduce LDL cholesterol by 5-25% and increase HDL cholesterol. It works by decreasing VLDL synthesis in the liver, reducing lipolysis in adipose tissue, and boosting lipoprotein lipase activity.

Statins are a class of drugs that inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis. This leads to a reduction in LDL cholesterol levels.

Plant stanols are plant-derived compounds that are structurally similar to cholesterol, but lack a double bond on their B ring. They help reduce cholesterol levels by competing with it for absorption.

Plant sterols are plant-derived compounds with a structure similar to cholesterol, but with different side chains. Like stanols, they can help lower cholesterol levels.

SREBPs (sterol regulatory element-binding proteins) are transcription factors that control the synthesis of HMG-CoA reductase, a key enzyme in cholesterol synthesis.

Cholesterol, an essential lipid, plays a crucial role in cell membranes and is the precursor to steroid hormones, bile acids, and vitamin D.

Cholesterol is composed of four fused hydrocarbon rings (A-D) forming a steroid nucleus. It features a hydroxyl group at C3, a double bond between C5 & C6, an eight-membered hydrocarbon chain at C17, and methyl groups at C10 & C13.

Dietary cholesterol and de novo synthesized cholesterol contribute to cellular cholesterol levels. Cholesterol homeostasis is maintained by balancing cholesterol influx and efflux.

HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, is regulated by transcription, protein degradation, and phosphorylation. Insulin activates the enzyme while glucagon inhibits it.

The lipid deposition in the endothelial linings of blood vessels can lead to plaque formation, causing narrowing of blood vessels (atherosclerosis).

Bile acids, synthesized from cholesterol in the liver, aid in fat digestion and absorption. They undergo enterohepatic circulation, being recycled and reabsorbed in the intestines.

De novo cholesterol synthesis involves multiple enzymatic steps starting with acetyl-CoA. HMG-CoA reductase is the rate-limiting enzyme, converting HMG-CoA to mevalonate.

Statins are medications that inhibit HMG-CoA reductase, reducing cholesterol synthesis and subsequently lowering LDL cholesterol levels.

Synthesized in the liver, stored and concentrated in the gallbladder, discharged into the gut, aiding in the absorption of lipids, cholesterol, and fat-soluble vitamins

The rate-limiting step of bile acid synthesis is performed by this enzyme, regulated by bile acid and salt concentration.

The majority of cholesterol circulating in the body is attached to long-chain fatty acids like oleic and linoleic acids, forming cholesterol esters.

ACAT is an enzyme found in the ER membrane that attaches fatty acids to cholesterol, primarily in the liver, forming cholesterol esters. Excess cholesterol gets stored as droplets in the cell.

LCAT is an enzyme that esterifies cholesterol associated with HDL outside of cells. This is important for cholesterol transport and metabolism.

The primary site of cholesterol synthesis is the liver, producing around 1 gram per day. Other sites include the intestine, adrenal cortex, ovaries, and testes. The brain synthesizes its own cholesterol, which is crucial for myelination.

Acetyl-CoA, a key component for cholesterol synthesis, is primarily produced within mitochondria. It's then transported to the cytosol in the form of citrate.

Mevalonate is a crucial intermediate in cholesterol synthesis. It's synthesized from Acetyl-CoA in the cytosol before being transported to the ER for further processing.

Pyruvate dehydrogenase converts glucose to pyruvate, which then gets converted into Acetyl-CoA. Ethanol, when consumed, can also be converted into Acetyl-CoA, contributing to cholesterol synthesis.

Cholesterol synthesis involves numerous steps that require various components. Besides Acetyl-CoA, the process needs 16 NADPH, 36 ATP, and oxygen.

Cholesterol synthesis is highly regulated to ensure proper balance in the body. The key enzyme, HMG-CoA reductase, is controlled by various mechanisms: transcription, protein degradation, and covalent modification.

Bile salts are steroid derivatives produced by the liver that emulsify lipids, breaking them down into smaller droplets for easier absorption in the watery environment of the gut.

Hormonal regulation of HMG-CoA reductase activity involves phosphorylation and dephosphorylation. Glucagon, released when blood sugar is low, activates phosphorylation, inactivating the reductase, while insulin promotes dephosphorylation, activating it.

By inhibiting cholesterol synthesis, statins reduce intracellular cholesterol levels. This triggers the upregulation of LDL receptors on cells, leading to increased removal of LDL from the bloodstream.

Plant stanols and sterols are plant-derived compounds with similar structures to cholesterol. They inhibit cholesterol absorption in the gut, effectively lowering cholesterol levels.

Bile acid sequestrants are medications that bind to bile acids in the intestine, preventing their reabsorption and reducing LDL levels by increasing hepatic bile acid synthesis.