Rosiglitazone improves characteristics of Non‐Alcoholic Steatohepatitis (NASH) in a mouse model of metabolic syndrome

Abstract

NASH, which is closely associated with metabolic syndrome (MS), is the most common cause of chronic liver disease in the Western world, but has no approved treatment. Middle‐aged (MA, 12‐month) male LDLR−/− mice fed 3 months of high‐fat diet (HFD) develop MS (obesity, elevated fasting glucose and triglycerides, and decreased HDL), and reveal a classical NASH phenotype of liver steatosis, inflammation and fibrosis. We hypothesized that treatment with the insulin‐sensitizer rosiglitazone (RSG) could prevent NASH by attenuating MS development and age‐related oxidative stress. RSG treatment dramatically reduced, but did not completely prevent, steatosis in HFD‐fed MA LDLR−/− mice. RSG reversed HFD‐mediated decreases in liver fatty acid oxidation genes (CPT1, ACADm, HADHa), and attenuated HFD‐induced decreases in antioxidant genes (DJ‐1, Nrf2, NQO1, SOD2, GPX‐1 and ‐4). But RSG had no effect on HFD‐generated increases in fibrosis genes (Coll1α2, Coll4α1 and TGF‐β1) or inflammation genes (MCP‐1, TNFα, CD68). RSG‐treatment of palmitate‐treated primary hepatocytes showed that RSG increased expression of both fatty acid oxidation and synthesis genes. RSG induced β‐oxidation in liver mitochondria, as seen by increased respiratory control ratios and ADP to ATP conversion with palmitoyl‐carnitine. RSG may thus prevent steatosis, at least partially, through direct effects to promote hepatocyte β‐oxidation.