Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis

Abstract

Low levels of serum adiponectin have been reported to be associated with obesity, diabetes, and non-alcoholic steatohepatitis (NASH), as well as several malignancies. Adiponectin knockout (KO) mice have been reported to cause insulin resistance and neointimal formation of the artery. We used adiponectin KO mice fed a high fat (HF) diet, and investigated the effect of adiponectin on the progression of steatohepatitis and carcinogenesis in vivo. Adiponectin KO mice and wild type (WT) mice were fed a HF diet or normal chow for the periods of 24 and 48 weeks. The HF diet contained 60% of calories from fat. The adiponectin KO mice on the HF diet showed obesity, marked elevation of serum transaminase levels, and hyperlipidemia. At 24 weeks, hepatic expression of tumor necrosis factor-alpha and procollagen alpha (I) was higher in KO mice as compared with WT mice. At 48 weeks, liver triglyceride contents in KO mice on normal chow were significantly higher than those in WT mice. Hepatocyte ballooning, spotty necrosis, and pericellular fibrosis around central veins were observed in KO mice on the HF diet. The pericellular fibrosis was more severe in KO mice on the HF diet than that in WT mice (1.62% vs 1.16%, P = 0.033). Liver adenoma and hyperplastic nodules developed in a KO mouse on the HF diet at 48 weeks (12.5%, n = 1/8), whereas no tumor was detected in WT mice (n = 10). Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-alpha expression and liver fibrosis.