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Context: The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the functionally active amino acid exchange in humans Gly388Arg (mouse homologue: Gly385Arg) in the fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid and glucose metabolism, may determine the dynamics of hepatic lipid accumulation and insulin sensitivity in humans. Mechanisms of this substitution were studied in mice under normal chow and high-fat diet.; Design: In humans the Gly388Arg polymorphism was studied for its relationship with the change of liver fat content and insulin sensitivity during 9 month of a lifestyle intervention. We also studied a knock-in mouse strain with an Arg385 allele introduced into the murine FGFR4 gene under normal chow and high-fat diet.; Results: In humans, the FGFR4Arg388 allele did not associate with liver fat content or insulin sensitivity in overweight and obese subjects before the lifestyle intervention. However, it associated with less decrease of liver fat content and less increase of insulin sensitivity during the intervention. In mice, under normal chow, the FGFR4Arg385 allele associated with elevated hepatic triglyceride content, altered hepatic lipid composition, and increased hepatic expression of genes inducing de novo lipogenesis and glycolysis. Body fat mass and distribution, glucose tolerance and insulin sensitivity were unaltered. No effects of the FGFR4Arg385 allele on glucose or lipid metabolism were found under high-fat diet.; Conclusion: Our data indicate that the FGFR4Arg388(385) allele affects hepatic lipid and glucose metabolism specifically during a healthy caloric intake.
