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

• Published in: The journal of clinical endocrinology and metabolism Vol. 90; no. 7; pp. 4238 - 4243
• Main Authors: Stefan, Norbert, Schäfer, Silke, Machicao, Fausto, Machann, Jürgen, Schick, Fritz, Claussen, Claus D, Stumvoll, Michael, Häring, Hans-Ulrich, Fritsche, Andreas
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.07.2005
• Subjects: Adult; Biological and medical sciences; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Cross-Sectional Studies; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Humans; Insulin Resistance; Lipase - genetics; Lipid Metabolism; Liver - metabolism; Male; Medical sciences; Polymorphism, Genetic; PPAR gamma - genetics; Vertebrates: endocrinology; Visceral fat; Pancreatic hormone; Genetic variability; Digestive system; Enzyme; Liver; Triacylglycerol lipase; Genotype; Esterases; Insulin; Carboxylic ester hydrolases; Target tissue resistance; Hydrolases; Insulin resistance; Endocrinology; Polymorphism
• DOI: 10.1210/jc.2004-2479
• ISSN: 0021-972X

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-γ2 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-γ2. These findings may be relevant for intervention strategies to prevent increase in liver fat content and insulin resistance.