Rate limiting step in cholesterol synthesis is
Control of Cholesterol BiosynthesisSREBP Pathway The steps in the biosynthesis of cholesterol to HMG-CoA are reversible. The formation of mevalonate, however, in the next step is irreversible and is the committed step. Regulation of cholesterol biosynthesis is exeed near the beginning of the pathway at the HMG-CoA reductase step, the rate limiting step. The reduced synthesis of cholesterol in starving animals is accompanied by a decrease in the activity of the enzyme. However, it is only hepatic synthesis that is inhibted by dietary cholesterol. "HMG-CoA reductase" in liver is inhibited by mevalonate, the immediate product of the pathway and by cholesterol, the main product.SREBP: Cholesterol and metabolites repress transcription of the "HMG-CoA reductase" activation of a "sterol regulatory element-binding protein" (SREBP) transcription factor. SREBPs are a family of proteins that regulate the transcription of a range of genes involved in the cellular uptake and metabolism of cholesterol and other lipids.A second control point appears to be at the cyclisation of squalene and conversion to lanosterol, but details of the regulation at this step is not clear.Effect of starving/fasting: Fasting and/starvation also inhibit the enzyme and activate "HMG-CoA lyase" to form ketone bodies.Effect of feeding cholesterol: Feeding cholesterol reduces the hepatic biosynthesis of cholesterol by reducing the activity of "HMG-CoA reductase". Intestinal cholesterol biosynthesis does not respond to the feeding of high cholesterol diets.Role of hormonesInsulin: Increases HMG-CoA reductase activity. The hormone is required for the diurnal rhythm (diurnal variation) that occurs in cholesterol biosynthesis, a phenomenon probably related to feeding cycles and the need for bile acid synthesis.Glucagon and/glucocoicoids Decreases the activity of HMG-CoA reductase and reduce the cholesterol biosynthesis.Thyroid hormones: Stimulates HMG-CoA reductase activity.Role of cyclic AMP: HMG-CoA reductase may exist in active/inactive forms, which is reversibly modified by phosphorylation/and dephosphorylation mechanisms, which may be mediated by c-AMP dependent protein kinases. Cyclic AMP inhibits cholesterol biosynthesis by conveing "HMG-CoA reductase" to inactive form.Ref: M.N. Chatterjea - Textbook of Biochemistry, 8th edition, page no: 434
HMG CoA synthetase
HMG CoA reductase
Thiokinase
Mevalonate kinase
Metabolism of lipid