Transcriptional Control of Apolipoprotein A-I Gene Expression in Diabetes

Transcriptional Control of Apolipoprotein A-I Gene Expression in Diabetes Arshag D. Mooradian 1 , Michael J. Haas 1 and Norman C.W. Wong 2 1 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri 2 Department of Medicine and Biochemistry & Molecular Biology, University of Calgary, Alberta, Canada Address correspondence and reprint requests to Arshag D. Mooradian, MD, Division of Endocrinology, Saint Louis University, 1402 South Grand Blvd., Saint Louis, MO 63104. E-mail: mooradad{at}slu.edu Abstract Cardiovascular disease continues to be the leading cause of mortality in diabetes. One of the factors contributing to the increased risk is the high prevalence rate of low plasma concentrations of HDL cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein (apo) A-I. The reduced plasma concentrations of HDL could be the result of increased fractional clearance of HDL and reduced expression of apo A-I. In animal models of diabetes and in cell cultures treated with high concentrations of glucose, apo A-I expression is reduced. In this review we will discuss the alterations in transcriptional control of apo A-I in diabetes. The role of select nutritional and hormonal alterations commonly found in diabetes will be reviewed. Specifically, we will review the literature on the effect of hyperglycemia, hypoinsulinemia, and ketoacidosis, as well as the role of various mediators of insulin resistance, such as fatty acids, cytokines, and prostanoids, on apo A-I promoter activity. Identifying the mechanisms that modulate apo A-I gene expression will aid in the new development of therapeutic agents that increase plasma apo A-I and HDL concentrations. apo, apolipoprotein CHD, coronary heart disease COX, cyclooxygenase CVD, cardiovascular disease FFA, free fatty acid HNF, hepatocyte nuclear factor IL, interleukin IRCE, insulin response core element nTRE, negative thyroid hormone response element pH-RE, pH-responsive element PKC, protein kinase C PMA, phorbol myristate acetate TNF-α, tumor necrosis factor-α UKPDS, U.K. Prospective Diabetes Study VA-HIT, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Footnotes Accepted November 5, 2003. Received August 20, 2003. DIABETES