Atorvastatin Dose-Dependently Decreases Hepatic Lipase Activity in Type 2 Diabetes

Abstract

OBJECTIVE -Hepatic lipase (HL) is involved in the metabolism of several lipoproteins and may contribute to the atherogenic lipid profile in type 2 diabetes. Little is known about the effect of cholesterol synthesis inhibitors on HL activity in relation to sex and the hepatic lipase gene, the LIPC promoter variant in type 2 diabetes. Therefore, we studied the effect of atorvastatin 10 mg (A10) and 80 mg (A80) on HL activity in 198 patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -Patients (aged 45-75 years, without manifest coronary artery disease, total cholesterol 4.0 -8.0 mmol/l, and fasting triglycerides [TG] 1.5-6.0 mmol/l) were included in a double-blind, randomized, placebo-controlled trial for 30 weeks (Diabetes Atorvastatin Lipid Intervention study).RESULTS -HL activity at baseline was significantly higher in our population compared with an age-matched control group without type 2 diabetes (406 Ϯ 150 vs. 357 Ϯ 118 units/l). HL activity in men versus women (443 Ϯ 158 vs. 358 Ϯ 127 units/l), in carriers of the LIPC C/C allele versus carriers of the T/T allele (444 Ϯ 142 vs. 227 Ϯ 96 units/l), and in Caucasians versus blacks (415 Ϯ 150 vs. 260 Ϯ 127 units/l) all differed significantly (P Ͻ 0.001). Atorvastatin dose-dependently decreased HL (A10, Ϫ11%; A80, Ϫ22%; both P Ͻ 0.001). Neither sex nor the LIPC C3 T variation influenced the effect of atorvastatin on HL activity.CONCLUSIONS -Sex, LIPC promoter variant, and ethnicity significantly contribute to the baseline variance in HL activity. Atorvastatin treatment in diabetic dyslipidemia results in a significant dose-dependent decrease in HL activity, regardless of sex or the LIPC promoter variant. Diabetes Care 26:427-432, 2003H epatic lipase (HL) is involved in the metabolism of several lipoproteins (1) and is a key player in HDL metabolism (2,3). Hydrolysis of phospholipids and triglycerides by HL leads to the conversion of large, buoyant HDL2 to small, dense HDL3 and may induce cholesterol (ester) flux to the liver (4,5). In this way, HL is involved in reverse cholesterol transport and is a major determinant of plasma HDL concentration (6,7). HL also plays a role in the formation of small, dense LDL and contributes to the expression of the LDL subclass phenotype (8,9). Finally, HL is proposed to be involved in postprandial lipid clearing (10). Obviously, HL activity seems to be central in the metabolism of lipoproteins strongly associated with coronary artery disease (CAD) risk in type 2 diabetes. Zambon et al. (11) identified HL as a focal point for the development and treatment of CAD. Genetic variation, sex, and abdominal fat mass affect HL activity in humans (12-15).In the human hepatic lipase gene (LIPC), variants are found that affect lipase activity (16 -18). Besides rather rare variants leading to complete HL deficiency (19,20), common base substitutions in the proximal LIPC promoter affect HL activity up to twofold (15,21,22). Four base substitutions, Ϫ250 G3 A, Ϫ514 C3 T, Ϫ710 T3 C, and Ϫ763 A3 G, were found to be completely linked (2...

Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database

“…Statins have also been reported to reduce activity of hepatic lipase ( 18 ). In the case of atorvastatin, this effect is positively dose dependent over the 20-80 mg dose range ( 18 ).…”

Molecular Mechanisms of HDL-Cholesterol Elevation by Statins and Its Effects on HDL Functions

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