Liver-Specific Overexpression of 17ß-HSD13 Causes Hepatic Steatosis in Mice

Abstract

According to our previous study, considerable evidences showed that a liver lipid droplet-associated protein 17β-HSD13 contribute to the development of liver disease. To understand the basis for this, we generated and studied transgenic mice that express human hsd17b13 specifically in hepatocytes (L-h17B13 mice).We examined the hepatic expression of several genes involved in fatty acid synthesis and oxidation in L-h17B13 mice. mRNA levels of three enzymes involved in fatty acid synthesis (SREBP-1c, fatty acid synthase [FAS], and ACC) were significantly increased L-h17B13 mice. The mRNA levels of peroxisome proliferator-activated receptor α (PPARα), a transcription factor that promotes fatty acid oxidation and its target gene, acyl-CoA oxidase (ACOX) and medium-chain acyl-CoA dehydrogenase (MCAD), also higher in L-h17B13 mice. mRNA levels of carnitine palmitoyltransferase (CPT1a), a protein involved in translocating fatty acids into the mitochondria for oxidation, was higher in L-h17B13 mice. ApoB, a lipid secretion related gene, was markedly reduced in L-h17B13 mice. Strikingly, male liver-specific h17β-HSD13 mice fed a standard chow diet display significantly elevated hepatic triglyceride levels at 3-4 months of age compared to matched littermate controls. When mice were fed a high-fat diet, this hepatic phenotype, as well as other metabolic phenotypes (obesity and glucose intolerance), worsened. Our investigations establish that 17β-HSD13 specifically overexpressed in mice hepatocytes induces hepatic steatosis and metabolic disorders. Disclosure W. Su: None. Y. Guan: None.