Regulation of Cholesterol

Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake in food leads to a net decrease in endogenous production and vice versa.

The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig-1.

When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low.

The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the “Sterol Regulatory Element” of a number of genes to stimulate their transcription. Amongst the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, while HMG-CoA reductase leads to an increase of endogenous production of cholesterol.

A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985.

The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. A study by Ockene et al. showed that there are seasonal variations in cholesterol levels in humans, more on average in winter.

Function

Cholesterol is an important component of the membranes of cells, providing stability; it makes the membrane’s fluidity stable over a bigger temperature interval. The hydroxyl group on cholesterol interacts with the phosphate head of the membrane and the bulky steroid and the hydrocarbon chain is embedded in the membrane.

It is the major precursor for the synthesis of vitamin D, of the various steroid hormones, including cortisol, cortisone, and aldosterone in the adrenal glands, and of the sex hormones progesterone, estrogen, and testosterone.

The presence of cholesterol has a direct effect on the fluidity of the membrane. Further recent research shows that cholesterol has an important role for the brain synapses as well as in the immune system, including protecting against cancer.

Excretion

Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecitin and bilirubin gallstones also occur less frequently.