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Long-Term Regulation of Cholesterol Synthesis


HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the synthesis of cholesterol can be regulated via transcriptional control. Transcriptional control starts with a complex that is sequestered in the endoplasmic reticulum.

The initial catalyst causes secretory proteins to move part of the complex to the Golgi apparatus where the regulatory molecule can be released to travel to the nucleus and activate transcription of HMG-CoA reductase.

When cholesterol levels are high, both a sterol and the protein Insig bind to

to inhibit the release of the regulatory molecule.

When cholesterol levels are low, Insig is ubiquitinated and the secretory molecule move the remaining complex components to the Golgi apparatus. Once there, a pair of proteases act to release the nuclear-targeted regulatory domain of


This regulatory component then makes its way to the nucleus where is specifically binds to a

to activate gene transcription.