Cholesterol Biosynthesis

Cholesterol is an essential component of cell membranes and a precursor of bile acids and steroid hormones. Regardless of its complicated chemical structure, it is not essential for humans. Primarily in the liver, but also in the intestine and skin, the body makes its own cholesterol in a controlled fashion in amounts sufficient to cover its needs.

Isoprenoid synthesis (A) begins with the condensation of three molecules of acetyl-CoA to 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA). The enzyme HMG-CoA-synthase (1) is also involved in the formation of ketone bodies. However, isoprenoid synthesis does not occur inside the mitochondria but in the endoplasmic reticulum (ER). Subsequent removal of CoA by HMG-CoA-reductase (2) results in meval-onate. This is the key enzyme of cholesterol biosynthesis and is subject to several regulatory mechanisms. For instance, insulin and thyroxin stimulate its activity, whereas exogenous gluca-gon and cholesterol have inhibitory effects. Mevalonate is decarboxylated to isopentenyl diphosphate (IPP) by mevalonate kinase (3). IPP is also termed active isoprene. It is the basic building block of all iso-prenoids (C5 building block). Further condensation of these basic building blocks is species-specific. A multitude of isoprenoids (particularly long-chain) can only be synthesized by plants (e. g., carotenoids, tocopherols), some only by specific plant families (e. g., caoutchouc). For animals, synthesis of the cyclic isoprenoid cholesterol (6 IPP-units) is of utmost importance. IPP can be converted to farnesyl diphosphate via several intermediates (4). Since it is still a molecular chain, molecules with long side-chains may form at this point through further condensation with IPP. These molecules often function as "anchors" inside the lipophilic cell membrane. For instance, dolichol, with its long side-chain (~90 C-atoms), is the lipid anchor for glycoproteins in the ER. Finally, head-to-head reaction of two farnesyl diphosphate molecules leads to the formation of squalene, which is cyclized via the epoxide structure and turns into cholesterol after modification by cytochrome P450 enzymes.

Cholesterol may be released directly into the gall bladder by hepatocytes or enzymatically modified into bile acids. Integrated in lipoproteins, it can be transported to hormone-synthesizing gland cells and used to synthesize steroid hormones such as cortisol, progesterone, estradiol, testosterone, and aldosterone.

Due to the significance of hypercholes-terolemia for the pathogenesis of various diseases, regulation of cholesterol biosynthesis is the focus of intense research. Transcriptional control of a diversity of enzymes involved in this biosynthesis is of particular interest. Expression can be triggered by various stimuli, e.g., cholesterol levels, expression of LDL receptors, or, more generally, by dietary composition. Additionally, these different factors may interact with one another.

- A. Cholesterol Biosynthesis -

Glucagon

Insulin Thyroxine

Acetyl-CoA

HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA)

  • HMG-CoA reductase (5)|
  • Mevalonate

Mevalonate kinase O |

Mevalonate diphosphate

^Isopentenyl diphosphate (IDP)

Geranyl diphosphate

Farnesyl diphosphate synthase

—Farnesyl diphosphate Squalene synthase

Squalene

Squalene epoxidase

  • Squalene epoxide
  • syl d iph <§j

-Squale

Lanosterol-14 a-demethylase

Acetoacetyl-CoA

IDP i

Isopentenyladenine

Heme A Ubiquinone Dolichol Prenylated proteins

Squalene diepoxide

Squalene oxidocyclase

Lanosterol

Lanosterol-14 a-demethylase

Cholesterol-7a-hydroxylase

Demosterol

Cholesterol

24(S),25-oxidolano-sterol (OLAN)

24(S),25-epoxy-cholesterol

Bile cholesterol

Bile salts

Lipoproteins

Steroid hormones

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