Liver fat and insulin resistance are independently associated with the -514C>T polymorphism of the hepatic lipase gene.
BACKGROUND
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-gamma(2) on liver fat content and insulin sensitivity.


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-gamma(2). These findings may be relevant for intervention strategies to prevent increase in liver fat content and insulin resistance.
Stefan
Norbert
N
Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, University of Tübingen, Germany. norbert.stefan@med.uni-tuebingen.de
Schäfer
Silke
S
Machicao
Fausto
F
Machann
Jürgen
J
Schick
Fritz
F
Claussen
Claus D
CD
Stumvoll
Michael
M
Häring
Hans-Ulrich
HU
Fritsche
Andreas
A
D000328:Adult; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008049:Lipase / Q000235:genetics*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D047495:PPAR gamma / Q000235:genetics; D011110:Polymorphism, Genetic
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C504173:LIPC protein, human; D047495:PPAR gamma; D008049:Lipase