This proposal will examine the causes of primary hypercholesterolemia (nonfamilial hypercholesterolemia), and it will develop a step-care approach to therapy of this condition. One hundred and sixty patients with primary hypercholesterolemia will be studied. They will first be studied by isotope-kinetic techniques to determine their underlying physiological defect, whether decreased receptor-mediated clearance of LDL, reduced affinity of LDL for receptors, or overproduction of LDL. Family studies will be carried out to determine whether the hypercholesterolemia in some families is inherited as a monogenic disorder. If evidence is obtained for the latter, the underlying metabolic defect will be sought, namely, an abnormality in the primary structure of apolipoprotein B, a reduced ability of cells to generate LDL receptors, an overabsorption of cholesterol, a decreased synthesis of bile acids, or a failure to catabolize saturated fatty acids. In patients with overproduction of LDL, several studies will be done including the composition and lipoprotein content of apolipoprotein E, the interaction of VLDL with cells in culture (fibroblasts and macrophages), and the physical characteristics of LDL. Patients with primary hypercholesterolemia will then enter into a treatment program. The first phase will be diet in which the effectiveness of diets low in fat and high in monounsaturated fats will be compared. The next step will be to study the additional benefit from drugs used in low doses to inhibit the absorption of cholesterol (sitostanol) and bile acids (cholestyramine). Finally, these regimens will be compared to HMG CoA reductase inhibitors (mevinolin). As a last study, the mechanisms of action of mevinolin and cholestyramine will be compared in patients with reduced clearance of LDL, while mevinolin and nicotinic acid will be compared in patients with overproduction of LDL.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL029252-06
Application #
3563701
Study Section
Metabolism Study Section (MET)
Project Start
1982-09-30
Project End
1992-09-29
Budget Start
1987-09-30
Budget End
1988-09-29
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
Shah, Meena; Adams-Huet, Beverley; Bantle, John P et al. (2005) Effect of a high-carbohydrate versus a high--cis-monounsaturated fat diet on blood pressure in patients with type 2 diabetes. Diabetes Care 28:2607-12
Abate, Nicola; Chandalia, Manisha; Snell, Peter G et al. (2004) Adipose tissue metabolites and insulin resistance in nondiabetic Asian Indian men. J Clin Endocrinol Metab 89:2750-5
Abate, Nicola; Carulli, Lucia; Cabo-Chan Jr, Alberto et al. (2003) Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab 88:5927-34
Chandalia, M; Garg, A; Lutjohann, D et al. (2000) Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med 342:1392-8
Toto, R D; Grundy, S M; Vega, G L (2000) Pravastatin treatment of very low density, intermediate density and low density lipoproteins in hypercholesterolemia and combined hyperlipidemia secondary to the nephrotic syndrome. Am J Nephrol 20:7-Dec
Guerra, R; Wan, Y; Jia, A et al. (1999) Testing for linkage under robust genetic models. Hum Hered 49:146-53
Weiner, M F; Vega, G; Risser, R C et al. (1999) Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease. Biol Psychiatry 45:633-8
Bersot, T P; Vega, G L; Grundy, S M et al. (1999) Elevated hepatic lipase activity and low levels of high density lipoprotein in a normotriglyceridemic, nonobese Turkish population. J Lipid Res 40:432-8
Chandalia, M; Abate, N; Garg, A et al. (1999) Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men. J Clin Endocrinol Metab 84:2329-35
Vega, G L; von Bergmann, K; Grundy, S M et al. (1999) Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol. J Intern Med 246:1-9

Showing the most recent 10 out of 138 publications