Biosynthesis of Cholesterol

Flashcards covering the biosynthesis, regulation, functions, and metabolism of cholesterol and its derivatives based on lecture notes.

Functions of cholesterol

A component of mammalian cell membranes and a precursor for bile acids, steroid hormones, and Vitamin D.

Disorders of cholesterol metabolism

Cardiovascular disease and gall stones.

Cholecystogram

An ultrasound of the gall bladder used to detect gall stones which are not visible on xray.

Endogenous cholesterol synthesis

Approximately $70\%$ of the cholesterol in the body which is synthesized within the cells.

Exogenous cholesterol sources

The $30\%$ of cholesterol derived from animal dietary sources such as eggs, meat, and milk.

Typical Western diet cholesterol intake

$500-2000\,mg/day$.

Main site of cholesterol synthesis

The liver is the primary location, though the intestine, adrenal cortex, and gonads also synthesize it.

Energetic cost of cholesterol production (Acetyl CoA)

The biosynthesis requires $18$ moles of acetyl CoA.

Energetic cost of cholesterol production (ATP)

The biosynthesis requires $18$ moles of ATP.

Energetic cost of cholesterol production (NADPH)

The biosynthesis requires $16$ moles of NADPH.

HMG-CoA Reductase

The regulatory enzyme for stage 1 of cholesterol synthesis that converts HMG-CoA to Mevalonate in the cytosol.

Mevalonate

The product of the first stage of cholesterol synthesis formed from three molecules of acetyl CoA.

Farnesyl pyrophosphate

The final active isoprenoid unit formed in stage 2 from mevalonate.

Precursor of Ubiquinone (Coenzyme Q10)

Farnesyl pyrophosphate serves as a precursor for this compound as well as cholesterol.

Squalene Synthase

The enzyme found in the endoplasmic reticulum that condenses two molecules of farnesyl pyrophosphate to form squalene.

Squalene

A linear molecule capable of folding into a ring during the third stage of cholesterol synthesis.

Lanosterol

The sterol formed from the cyclization of squalene in the fourth stage of synthesis.

HMG-CoA Reductase Allosteric Inhibitors

Glucagon, cortisol (glucocorticoids), and increased concentrations of cholesterol.

HMG-CoA Reductase Allosteric Activators

Insulin and thyroid hormones (T3).

Primary hormone increasing HMG-CoA Reductase activity

Insulin.

Lifestyle effects elevating blood cholesterol

High blood pressure, smoking, male gender, abdominal obesity, lack of exercise, and drinking soft water versus hard water.

Lifestyle effects elevating Free Fatty Acids (FFAs)

Emotional stress, cigarette smoking, coffee drinking, and eating few large meals rather than many small meals.

Statin drugs

A class of drugs including Lipitor, Zocor, and Provochol that inhibit HMG-CoA Reductase.

Statin drug side effect

Inhibits the synthesis of Coenzyme Q10 (ubiquinone), requiring a recommended supplementation of $100\,mg/day$.

Microsomal 7 alpha hydroxylase

The regulatory enzyme that synthesizes bile acids from cholesterol in the liver.

Primary bile acids

Cholic acid and chenodeoxycholic acid.

Secondary bile acids

Deoxycholic acid and lithocholic acid, produced in the intestine.

Coenzymes for bile acid synthesis

NADPH, $O_2$, cytochrome P450, and Vitamin C.

Hepatocrinin

The hormone responsible for secreting bile from the liver.

Cholecystokinin

The hormone that triggers the emptying of the bile duct from the gallbladder into the duodenum.

Enterohepatic Circulation

The portal circulation through which up to $98\%$ of bile acids and salts are reabsorbed from the intestines.

Cholesterol elimination volume

$1$ gram of cholesterol is eliminated in the feces daily, consisting of $50\%$ bile acids and $50\%$ cholesterol.

Coprostanol

The form of cholesterol resulting from bacterial conversion in the gut prior to excretion.

Vitamin C deficiency in guinea pigs

Leads to cholesterol accumulation and atherosclerosis due to decreased activity of $7$ alpha hydroxylase.

Oat bran mechanism

Binds cholesterol and bile acids, facilitating their excretion in the feces to decrease LDL.

Steroid hormone synthesis starting point

The conversion of cholesterol to progesterone.

Progesterone derivatives

Cortisol, androstenedione, and testosterone.

DHEA

Dehydroepiandrosterone; an alternate route intermediate from pregnenolone used to produce androstenedione.

Acyl Coenzyme A:cholesterol acyl transferase (ACAT)

An enzyme that decreases intracellular free cholesterol by promoting its esterification.

Cholesterol ester hydrolase

An enzyme that increases intracellular free cholesterol concentration by hydrolyzing cholesterol esters.