Hepatic Steatosis as a Result of Altered Lipid Metabolism in Mice with Adipocyte-specific Fatp4-deficiency under High-fat Diet

Introduction: Fatp4 (fatty acid transport protein 4) is expressed in adipose tissue and exhibits acyl-CoA synthetase activity for long chain fatty acids (LCFA). Its role in cellular fatty acid uptake, metabolism as well as its localization are still controversial. Aims: To characterize Fatp4 functions in adipocytes in vivo, we generated a mouse line with adipocyte-specific inactivation of the Fatp4 gene (aP2-cre). Methods: As under standard conditions mutant mice showed no phenotypical aberrance, they were then exposed to a high-fat diet enriched in LCFA. Adipose and liver tissues were assessed histologically. Uptake of radiolabeled palmitic and lignoceric acid into adipose tissue was measured. Lipid composition in adipose and liver tissue was quantified by GC/MS. Results: Fatp4 mutant mice on high-fat diet gained more body weight compared to wild-type although they were not consuming more food. Pronounced obesity was matched by thicker layer of subcutaneous fat, greater adipocyte circumference and increased total lipid contents. The latter was contrasted by a significant decrease in various phospholipids, sphingomyelin and cholesterol esters. Expression of genes involved in de novo lipogenesis and lipolysis was not altered. The uptake of radiolabeled palmitic and lignoceric acid was undisturbed. Livers of Fatp4 deficient animals under high-fat diet showed a higher degree of fatty degeneration and contained elevated levels of total lipids. No evidence for changes in insulin sensitivity and adipose inflammation was found. Conclusions: Fatp4 is not crucial for fatty acid uptake into adipocytes. In contrast, adipocyte-specific Fatp4 deficiency results in adipose hypertrophy and hepatic steatosis without impairment of insulin sensitivity. Our data demonstrate a critical role of Fatp4 in the synthesis of complex lipids in adipocytes, and FATP4 deficiency causes an overspill of adipose lipids which contribute to hepatic steatosis.

adiposity - fatty acid transport protein - fatty liver - lipid metabolism