Regulation of the expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by the major end product of the biosynthetic pathway, cholesterol, and by various hormones is critical to maintaining constant serum and tissue cholesterol levels in the face of an ever-changing external environment. The ability to downregulate this enzyme provides a means to buffer the body against the serum cholesterol-raising action of dietary cholesterol. The higher the basal expression of hepatic HMG-CoA reductase, the greater the "cholesterol buffering capacity" and the greater the resistance to dietary cholesterol. This review focuses on the mechanisms of feedback and hormonal regulation of HMG-CoA reductase in intact animals rather than in cultured cells and presents the evidence that leads to the proposal that regulation of hepatic HMG-CoA reductase acts as a cholesterol buffer. Recent studies with animals have shown that feedback regulation of hepatic HMG-CoA reductase occurs at the level of translation in addition to transcription. The translational efficiency of HMG-CoA reductase mRNA is diminished through the action of dietary cholesterol. Oxylanosterols appear to be involved in this translational regulation. Feedback regulation by dietary cholesterol does not appear to involve changes in the state of phosphorylation of hepatic HMG-CoA reductase or in the rate of degradation of this enzyme. Several hormones act to alter the expression of hepatic HMG-CoA reductase in animals. These include insulin, glucagon, glucocorticoids, thyroid hormone and estrogen. Insulin stimulates HMG-CoA reductase activity likely by increasing the rate of transcription, whereas glucagon acts by opposing this effect. Hepatic HMG-CoA reductase activity undergoes a significant diurnal variation due to changes in the level of immunoreactive protein primarily mediated by changes in insulin and glucagon levels. Thyroid hormone increases hepatic HMG-CoA reductase levels by acting to increase both transcription and stability of the mRNA. Glucocorticoids act to decrease hepatic HMG-CoA reductase expression by destabilizing reductase mRNA. Estrogen acts to increase hepatic HMG-CoA reductase activity primarily by stabilizing the mRNA. Deficiencies in those hormones that act to increase hepatic HMG-CoA reductase gene expression lead to elevations in serum cholesterol levels. High basal expression of hepatic HMG-CoA reductase, whether due to genetic or hormonal factors, appears to result in greater cholesterol buffering capacity and thus increased resistance to dietary cholesterol.

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Abstract. Regulation of the expression of hepatic 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase by the major end product of the biosynthetic pathway, cholesterol, and by various hormones is critical to maintaining constant serum and tissue cholesterol levels in the face of an ever‐changing external environment. The ability to downregulate this enzyme provides a means to buffer the body against the serum cholesterol–raising action of dietary cholesterol. The higher the basal expression of hepatic HMG‐CoA reductase, the greater the “cholesterol buffering capacity” and the greater the resistance to dietary cholesterol. This review focuses on the mechanisms of feedback and hormonal regulation of HMG‐CoA reductase in intact animals rather than in cultured cells and presents the evidence that leads to the proposal that regulation of hepatic HMG‐CoA reductase acts as a cholesterol buffer. Recent studies with animals have shown that feedback regulation of hepatic HMG‐CoA reductase occurs at the level of translation in addition to transcription. The translational efficiency of HMG‐CoA reductase mRNA is diminished through the action of dietary cholesterol. Oxylanosterols appear to be involved in this translational regulation. Feedback regulation by dietary cholesterol does not appear to involve changes in the state of phosphorylation of hepatic HMG‐CoA reductase or in the rate of degradation of this enzyme. Several hormones act to alter the expression of hepatic HMG‐CoA reductase in animals. These include insulin, glucagon, glucocorticoids, thyroid hormone and estrogen. Insulin stimulates HMG‐CoA reductase activity likely by increasing the rate of transcription, whereas glucagon acts by opposing this effect. Hepatic HMG‐CoA reductase activity undergoes a significant diurnal variation due to changes in the level of immunoreactive protein primarily mediated by changes in insulin and glucagon levels. Thyroid hormone increases hepatic HMG‐CoA reductase levels by acting to increase both transcription and stability of the mRNA. Glucocorticoids act to decrease hepatic HMG‐CoA reductase expression by destabilizing reductase mRNA. Estrogen acts to increase hepatic HMG‐CoA reductase activity primarily by stabilizing the mRNA. Deficiencies in those hormones that act to increase hepatic HMG‐CoA reductase gene expression lead to elevations in serum cholesterol levels. High basal expression of hepatic HMG‐CoA reductase, whether due to genetic or hormonal factors, appears to result in greater cholesterol buffering capacity and thus increased resistance to dietary cholesterol.

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