Editing Cholesterol (section)

===Regulation of cholesterol synthesis===
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the [[homeostasis|homeostatic]] mechanisms involved are only partly understood. A higher intake of food leads to a net decrease in endogenous production, whereas a lower intake of food has the opposite effect. The main regulatory mechanism is the sensing of [[intracellular]] cholesterol in the [[endoplasmic reticulum]] by the [[protein]] [[sterol regulatory element-binding protein|SREBP]] (sterol regulatory element-binding protein 1 and 2).<ref name="Espenshade_2007">{{cite journal | vauthors = Espenshade PJ, Hughes AL | title = Regulation of sterol synthesis in eukaryotes | journal = Annual Review of Genetics | volume = 41 | pages = 401–427 | year = 2007 | pmid = 17666007 | doi = 10.1146/annurev.genet.41.110306.130315 }}</ref> In the presence of cholesterol, SREBP is bound to two other proteins: [[SREBP cleavage-activating protein|SCAP]] (SREBP cleavage-activating protein) and [[INSIG-1]]. When cholesterol levels fall, INSIG-1 dissociates from the SREBP-SCAP complex, which allows the complex to migrate to the [[Golgi apparatus]]. Here SREBP is cleaved by S1P and S2P (site-1 protease and site-2 protease), two enzymes that are activated by SCAP when cholesterol levels are low.{{cn|date=December 2024}}

The cleaved SREBP then migrates to the nucleus and acts as a [[transcription factor]] to bind to the sterol regulatory element (SRE), which stimulates the [[Transcription (genetics)|transcription]] of many genes. Among these are the low-density lipoprotein ([[Low-density lipoprotein|LDL]]) receptor and [[HMG-CoA reductase]]. The LDL receptor scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase in endogenous production of cholesterol.<ref>{{cite journal | vauthors = Brown MS, Goldstein JL | title = The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor | journal = Cell | volume = 89 | issue = 3 | pages = 331–340 | date = May 1997 | pmid = 9150132 | doi = 10.1016/S0092-8674(00)80213-5 | s2cid = 17882616 | doi-access = free }}</ref> A large part of this signaling pathway was clarified by Dr. [[Michael S. Brown]] and Dr. [[Joseph L. Goldstein]] in the 1970s. In 1985, they received the [[Nobel Prize in Physiology or Medicine]] for their work. Their subsequent work shows how the SREBP pathway regulates the expression of many genes that control lipid formation and metabolism and body fuel allocation.{{cn|date=December 2024}}

Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain. The membrane domain senses signals for its degradation. Increasing concentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the [[proteasome]]. This enzyme's activity can also be reduced by phosphorylation by an AMP-activated protein [[kinase]]. Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low.<ref name="isbn0-7167-4955-6">{{cite book | vauthors = Tymoczko JL, Berg T, Stryer L, Berg JM | title = Biochemistry | publisher = W.H. Freeman | location = San Francisco | year = 2002 | pages = [https://archive.org/details/biochemistry200100jere/page/726 726–727] | isbn = 978-0-7167-4955-4 | url =https://archive.org/details/biochemistry200100jere| url-access = registration }}</ref>