Biochemistry, Cholesterol

Article Author:
Micah Craig
Article Editor:
Ahmad Malik
4/17/2019 11:23:37 PM
PubMed Link:
Biochemistry, Cholesterol


Cholesterol and its byproducts are important components of cell membranes as well as precursors to steroids, vitamin D, and bile acids.


Humans can both synthesize and absorb cholesterol via digestion. Once digested it is transported as a cholesterol ester (CE) through the digestive tract. It is also a key component of cellular membranes as it gives them rigidity by interspersing between phospholipids on the outer and inner cell membrane.[1][2][3]


Cholesterol synthesis, which occurs in the liver, takes place in both the cytoplasm and the smooth endoplasmic reticulum (SER). Once the liver synthesizes the cholesterol, it is packaged into lipoproteins. Lipoproteins are composed of various amounts of cholesterol, triacylglycerols, and phospholipids. There are several types of lipoproteins, all named by the amount of protein they contain and transport. Cholesterol, once synthesized is packaged into light density lipoproteins (LDLs) and delivered to the peripheral tissues. When it reaches the target tissue, the cell engulfs the LDL, and the cholesterol within is used as a structural component of the cell’s membrane or used to synthesize steroids or vitamin D.


The first step of biosynthesis of cholesterol involves 2 acetyl-CoA molecules which condense to form acetoacetyl-CoA. Next, a third molecule of acetyl-CoA is added by HMG CoA synthase, making HMG-CoA, a 6 carbon compound. Interestingly, these 2 reactions are similar to the reactions that occur to form ketone bodies. HMG-CoA reductase catalyzes the next step, which reduces HMG CoA to mevalonate. This is the rate-limiting step, meaning it is the one that controls whether the reaction continues in the forward direction. If sterol levels are abundant within the cell, a transcription factor downregulates the enzyme activity and visa versa. Next, there are a series of 8 reactions which ultimately convert mevalonate first to lanosterol, then finally to cholesterol.

There are 4 main ways that cholesterol synthesis is regulated, all at the level of HMG CoA reductase. The first, as previously mentioned, is via transcription factors which upregulate or downregulate the enzyme. Next, the enzyme is a sterol-sensing integral protein of the ER membrane so that when it senses high sterol levels, it binds to insig proteins leading to its ubiquitination or destruction. The third way HMG CoA reductase is regulated is covalently through the actions of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and a phosphoprotein phosphatase. The dephosphorylated form of the enzyme is active, while the phosphorylated form is inactive. Finally, the rate-limiting enzyme in cholesterol synthesis is also regulated hormonally by the actions of insulin, thyroxin, glucagon, and glucocorticoids. Insulin and thyroxin cause upregulation of the enzyme, while glucagon and the glucocorticoids have the opposite effect.


Cholesterol fulfills a number of biological functions and is necessary for successful human homeostasis. It not only acts as a precursor to bile acids, but it also assists in steroid and vitamin D synthesis as well as playing a central role in maintaining cellular membrane rigidity.

All classes of steroid hormones, glucocorticoids, mineralocorticoids, and the sex hormones, are derivatives of cholesterol. Synthesis occurs in the placenta and ovaries (estrogens and progestins), testes (testosterone) and adrenal cortex (cortisol, aldosterone, and androgens). The initial rate-limiting reaction converts cholesterol to pregnenolone, which is then oxidized and isomerized to progesterone, which is further modified in the ER and the mitochondria by various hydroxylation reactions to the other steroid hormones (cortisol, androgens, and aldosterone). Aldosterone acts primarily on the renal tubules where it stimulates potassium excretion and sodium and water uptake. Its ultimate effect is an increase in blood pressure. Cortisol allows the body to handle and respond to stress through its effects on intermediary metabolism, in other words, increased gluconeogenesis, and the inflammatory and immune responses. The androgens, specifically testosterone, estrogens, and progestins are responsible for sexual differentiation, libido, spermatogenesis, and the production of the ovarian follicles.

Vitamin D3 (cholecalciferol) from either the skin or the diet must be 25-hydroxylated in the liver from lipid-soluble compounds with a 4-ringed cholesterol backbone. It is then 1-hydroxylated to the active form 1,25-dihydroxycholecalciferol in the kidneys. Vitamin D then goes on to play an integral role in the terminal differentiation of hypertrophic chondrocytes and the subsequent calcification of the bone matrix.

Another function of cholesterol, as previously mentioned, is regulation of the fluidity of the plasma membrane which is important as fatty acid fluidity varies based on temperature. Cholesterol is found in the plasma membrane of cells in both inner and outer leaflets and decreases the fluidity close to the polar phospholipid heads with it steroid ring systems while at the same time increasing fluidity inside the bilayer with its generation of space.

Bile is a watery mixture of both inorganic and organic compounds, of which phosphatidylcholine and conjugated bile salts/acids are quantitatively the most important. Between 15 and 30 grams of bile salts/acids are secreted from the liver each day, but as a result of bile reabsorption, only about 0.5 grams are lost daily in the feces. As a result, to replace the amount lost, roughly 0.5 grams per day is synthesized from cholesterol in the liver. Cholesterol is incorporated in as the backbone in bile acid synthesis which is a complex multistep, multi-organelle process. This synthesis accomplishes 2 goals. First, it creates a way for the body to excrete cholesterol as there is no way to break it down physiologically and it allows lipids to be digested via emulsification and subsequent break down by pancreatic enzymes.

Clinical Significance

Cholesterol is a hot topic in the medical world as it not only has many functions, but elevated levels may hurt human physiology. It is implicated in many genetic diseases, cholelithiasis, and is also the target of many therapeutic pharmacologic drugs. The following is a summary of a few examples of its vast clinical significance.


The formation of gallstones occurs if there is either a bile salt deficiency or excess cholesterol secreted into the bile. In other words, when the liver secretes cholesterol, there must be a proper balance of bile salts, cholesterol, and phospholipids, as an imbalance causes cholesterol to precipitate. In pathologic states of hypercholesteremia, gallstones often are formed, which can then lead to cholecystitis or even ascending cholangitis. It was the understanding of this precarious relationship that led to the invention of 2 important types of antihyperlipidemic drugs: bile acid-binding resins (cholestyramine/colestipol/colesevelam) and cholesterol absorption inhibitors (ezetimibe). The former acts by blocking the reabsorption of bile acids in the small intestine which then forces the liver to synthesize more bile acids with the goal of using up excess cholesterol in the process, thus lowering serum cholesterol levels. Ezetimibe acts similarly by blocking absorption of cholesterol in jejunal enterocytes which then allows the body to take excess cholesterol and again secrete it into bile. It is interesting to note, that Fibrates, another class of antihyperlipidemic drugs, can cause cholelithiasis. This occurs simply by causing cholesterol excretion into bile, and as previously mentioned if there is excess cholesterol in bile it precipitates and forms stones.[4]


These are an important class of drugs used for the treatment of hyperlipidemia and hypercholesterolemia. They are HMG CoA analogs and act by reversible, competitive inhibition of HMG CoA Reductase, the rate-limiting enzyme in cholesterol synthesis. When serum cholesterol levels are too high, statins may be used to stop de novo synthesis in the liver.[5]


This is a result of an increased level of circulating LDL lipoproteins. LDLs are commonly referred to as the "bad" lipoproteins as they carry a very high concentration of cholesterol. When LDL levels are pathologically high, they are engulfed by macrophages, causing an accumulation of cholesterol esters within macrophages. This then leads to the transformation of macrophages into "foam" cells which ultimately results in the formation of atherosclerotic plaques within arteries. Plaque formation then leads to a disease state which includes elevated blood pressure and coronary artery disease.[6]

Type III Hyperlipoproteinemia

This is a genetic disease in which individuals are homozygotic for the Apo E-2 ligand resulting in defective clearance of chylomicrons, hypercholesterolemia, and premature atherosclerosis.[7]


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