Cholesterol Synthesis is Controlled by Regulation of HMG-CoA Reductase
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p262-263
2025-08-04
550
Cholesterol synthesis is tightly controlled by regulation at the HMG-CoA reductase step. The activity of the enzyme is inhibited by mevalonate, the immediate product of the reaction, and by cholesterol, the main product of the pathway. Thus, increased intake of cholesterol from the diet leads to a decrease in de novo synthesis, especially in the liver.
Regulatory mechanisms include both modulation of the syn thesis of enzyme protein and posttranslational modification. Cholesterol and metabolites repress transcription of HMG CoA reductase mRNA via inhibition 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. SREBP activation is inhibited by insulin-induced gene (Insig), a protein whose expression, as its name indicates, is induced by insulin and is present in the endoplasmic reticulum. Insig also promotes degradation of HMG-CoA reductase. A diurnal variation occurs both in cholesterol synthesis and reductase activity. Short term changes in enzyme activity, however, are brought about by posttranslational modification (Figure 1). Insulin or thyroid hormone increases HMG-CoA reductase activity, whereas glucagon or glucocorticoids decrease it. Activity is reversibly modified by phosphorylation–dephosphorylation mechanisms, some of which may be cAMP-dependent and therefore immediately responsive to glucagon. AMP-activated protein kinase (AMPK) (formerly called HM-CoA reductase kinase) phosphorylates and inactivates HMG-CoA reductase. AMPK is activated via phosphorylation by AMPK kinase (AMPKK)and by allosteric modification by AMP.
Fig1. Possible posttranslational mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Stimulatory (⊕ ) or inhibitory ( ⊖) effects are shown as dotted green or red arrows, respectively. (AMPK, AMP-activated protein kinase; AMPKK, AMP-activated protein kinase kinase.).
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