Gene C. Ness

University of South Florida

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Dayami Lopez

North Carolina Central University

Christopher M. Chambers

Dr. John T. Macdonald Foundation

Gerald Salen

Rutgers New Jersey Medical School

John W. Porter

University of Missouri

Sarah Shefer

Rutgers New Jersey Medical School

Ashok K. Batta

Rutgers, The State University of New Jersey

Lindsey R. Boone

University of South Florida

Laura C. Pendleton

University of South Florida

William R. Lagor

Baylor College of Medicine

Guorong Xu

Northwest University

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University of South Florida

Rutgers, The State University of New Jersey

Florida College

Rutgers New Jersey Medical School

Veterans Biomedical Research Institute

University of Wisconsin–Madison

Johns Hopkins University

United States Department of Veterans Affairs

University Hospital, Newark

National Institutes of Health

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Feedback and Hormonal Regulation of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase: The Concept of Cholesterol Buffering Capacity

Proceedings of The Society for Experimental Biology and Medicine (2000)

Gene C. Ness Christopher M. Chambers

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.

Coenzyme A

Hydroxymethylglutaryl-CoA reductase

10.1046/j.1525-1373.2000.22359.x

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Citations (159)

Influence of a naturally occurring competing enzymic activity on studies of 3-hydroxy-3-methylglutaryl coenzyme a reductase activity

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism (1979)

Gene C. Ness Mary H. Moffler

Coenzyme A

Hydroxymethylglutaryl-CoA reductase

Specific activity

10.1016/0005-2760(79)90049-3

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Citations (19)

Compensatory Responses to Inhibition of Cholesterol Absorption

The FASEB Journal (2006)

Gene C. Ness

Two experimental models that exhibit a high dependency on cholesterol absorption were investigated. These were diabetic and thyroidectomized rats fed 1% cholesterol. Feeding the 1% cholesterol diet to the thyroidectomized rats increased their serum cholesterol levels from 116 to 135 mg/dl while decreasing their low levels of hepatic HMG-CoA reductase protein to barely detectable levels. Adding 10 mg/kg/day of the cholesterol absorption inhibitor, ezetimibe, to the diet lowered serum cholesterol levels to 85 mg/dl and fully restored hepatic HMG-CoA reductase protein to normal levels. Hepatic LDL receptor protein was unaffected. Feeding cholesterol to diabetic rats increased serum cholesterol levels to over 500 mg/dl and nearly eliminated hepatic HMG-CoA reductase protein and mRNA. Administration of ezetimibe lowered serum cholesterol levels to actually less than normal and fully restored hepatic HMG-CoA reductase protein levels with little effect on hepatic reductase mRNA, indicating a posttranscription site of action. Again hepatic LDL receptor protein levels were unaffected. Changes in hepatic HMG-CoA reductase expression at a posttranscriptional site appear to be the major compensatory response to inhibition of cholesterol absorption. (Support from Merck/Schering Plough)

Hydroxymethylglutaryl-CoA reductase

Ezetimibe

10.1096/fasebj.20.4.a83-b

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Compensatory Responses to Inhibition of Hepatic Squalene Synthase

Archives of Biochemistry and Biophysics (1998)

Dayami Lopez Christopher M. Chambers R. Kennedy Keller Gene C. Ness

Squalene

10.1006/abbi.1997.0556

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Citations (21)

In vivo identification of response elements mediating thyroid hormone stimulation of hepatic HMG‐CoA reductase transcription

The FASEB Journal (2008)

Lindsey R. Boone Gene C. Ness

Hepatic HMG‐CoA reductase (HMGR) is the enzyme that catalyzes the rate‐limiting step in cholesterol biosynthesis. Thyroid hormone‐mediated stimulation of HMGR transcription is decreased in hypothyroid mammals and is increased about 5‐fold by subsequent treatment with triiodothyronine (T 3 ). We have utilized in vivo electroporation to introduce HMGR promoter‐luciferase constructs directly into livers of hypothyroid rats treated ±T 3 in an effort to identify the region(s) of the HMGR promoter responsible for this T 3 ‐mediated regulation. A linear relationship between HMGR promoter activity and serum T 3 levels was observed. The promoter was analyzed by in vivo electroporation out to −3190 bp. The functional T 3 response was localized to the proximal 325 bp, which exhibited a 5‐fold response to T 3 . Within this segment of the promoter, two response elements were identified: the SRE at −165 to −158 and the sequence AGGTCA at −316 to −321. EMSAs with liver nuclear extracts from T 3 −treated rats showed strong shifted bands with probes to both of these elements, which were not present in assays with liver nuclear extracts from hypothyroid rats. Antibody supershift assays revealed that SREBP‐2 bound to the SRE and that FTF/SHP, but not TRβ‐1 or LRH‐1, binds to the AGGTCA element at −316. These two regions appear to mediate the thyroid hormone response. (Supported in part by grant 04 TSP‐03 from the Florida Department of Health.)

Transcription

Thyroid hormone receptor

Response element

10.1096/fasebj.22.1_supplement.807.2

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Mechanism of Resistance to Dietary Cholesterol

Journal of Lipids (2011)

Lindsey R. Boone Patricia A. Brooks Melissa I. Niesen Gene C. Ness

Background. Alterations in expression of hepatic genes that could contribute to resistance to dietary cholesterol were investigated in Sprague-Dawley rats, which are known to be resistant to the serum cholesterol raising action of dietary cholesterol. Methods. Microarray analysis was used to provide a comprehensive analysis of changes in hepatic gene expression in rats in response to dietary cholesterol. Changes were confirmed by RT-PCR analysis. Western blotting was employed to measure changes in hepatic cholesterol 7α hydroxylase protein. Results. Of the 28,000 genes examined using the Affymetrix rat microarray, relatively few were significantly altered. As expected, decreases were observed for several genes that encode enzymes of the cholesterol biosynthetic pathway. The largest decreases were seen for squalene epoxidase and lanosterol 14α demethylase (CYP 51A1). These changes were confirmed by quantitative RT-PCR. LDL receptor expression was not altered by dietary cholesterol. Critically, the expression of cholesterol 7α hydroxylase, which catalyzes the rate-limiting step in bile acid synthesis, was increased over 4-fold in livers of rats fed diets containing 1% cholesterol. In contrast, mice, which are not resistant to dietary cholesterol, exhibited lower hepatic cholesterol 7α hydroxylase (CYP7A1) protein levels, which were not increased in response to diets containing 2% cholesterol.

Dietary Cholesterol

Reverse cholesterol transport

Lanosterol

10.1155/2011/101242

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Citations (29)

Technological advances in the study of HLA-DRA promoter regulation: Extending the functions of CIITA, Oct-1, Rb, and RFX

Acta Biochimica et Biophysica Sinica (2009)

Melissa I. Niesen Aaron Osborne William R. Lagor Harry Zhang Kristy Kazemfar

Several advances were established in examining the interaction of transcriptional factors with the HLA-DRA promoter. First, hydrodynamic injection was used to demonstrate the activation of the promoter by class II transactivator in a live mouse. Second, the Oct-1 DNA-binding site in the HLA-DRA promoter is a negative element in many cells, but here we show that Oct-1 activates the promoter independently of the Oct-1-binding site. Third, the retinoblastoma (Rb) protein is required for the induction of the endogenous HLA-DRA gene, due to a poorly understood, pleiotropic effect on the Oct-1 and YY1 repressive functions at the HLA-DRA promoter. There has never been an indication that direct promoter activation, by Rb, is possible. Here, we report that the first HLA-DRA intron has an Rb-responsive element, as indicated by a transient transfection/promoter reporter assay. Finally, RFX activates a methylated version of an HLA-DRA promoter reporter construct, consistent with the role of RFX in rescuing the expression of the methylated, endogenous HLA-DRA gene. Here, we report that this RFX function is not limited to a specific RFX-binding sequence or to the HLA-DRA promoter. These advances provide bases for novel investigations into the function of the major histocompatibility class II promoter.

CIITA

Response element

10.1093/abbs/gmp002

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Citations (2)

Reduced hepatic LDL-receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase and sterol carrier protein-2 expression is associated with pregnancy loss in the diabetic rat

Endocrine (1995)

Mark McLean Zhihong Zhao Gene C. Ness

Coenzyme A

10.1007/bf03000200

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Citations (9)