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Liver Fat and Insulin Resistance Are Independently Associated with the –514C>T Polymorphism of the Hepatic Lipase Gene

Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry (N.S., S.S., F.M., H.-U.H., A.F.), and Section on Experimental Radiology (J.M., F.S., C.D.C.), University of Tübingen, D-72076 Tübingen, Germany; and Department of Internal Medicine (M.S.), University of Leipzig, 100920 Leipzig, Germany

Address all correspondence and requests for reprints to: Norbert Stefan, M.D., Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. E-mail: norbert.stefan{at}med.uni-tuebingen.de.

Context: Liver fat predicts insulin resistance in humans. So far, there is not much information on genetic determinants of liver fat. Hepatic lipase is a liver-specific enzyme that regulates lipid metabolism.

Objective: First, our object was to investigate whether the functional –514C>T polymorphism of the hepatic lipase gene is associated with liver fat content and with insulin sensitivity. Second, because this polymorphism displays gene-nutrient interactions, we assessed gene-gene interactions with the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-₂ on liver fat content and insulin sensitivity.

Design and Methods: Cross-sectional data from a total of 1070 nondiabetic subjects were analyzed. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test. A subgroup of 115 subjects underwent measurements of liver fat.

Results: The –514C>T polymorphism of the hepatic lipase gene was associated with higher liver fat content (P = 0.005) and lower insulin sensitivity (P = 0.02), both after adjustment for age, gender, and percentage of body fat. This was independent of serum adiponectin concentrations (P = 0.01 and 0.03). However, there was an interaction of the –514C>T polymorphism with the Pro12Ala variant on liver fat (P = 0.09) and insulin sensitivity (P = 0.01). Subjects carrying the –514C>T polymorphism had higher liver fat content and were insulin resistant only before the background of the Pro/Pro genotype of the Pro12Ala polymorphism.

Conclusions: The –514C>T polymorphism of the hepatic lipase gene is associated with higher liver fat content and lower whole-body insulin sensitivity. However, these effects are modulated by the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-₂. These findings may be relevant for intervention strategies to prevent increase in liver fat content and insulin resistance.

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