Graduate School of Frontier Biosciences, Osaka University

Japanese

Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease

Journal Hepatology 64, 1994-2014 (2016)
Authors Satoshi Tanaka (1), Hayato Hikita (1), Tomohide Tatsumi (1), Ryotaro Sakamori (1), Yasutoshi Nozaki (1), Sadatsugu Sakane (1), Yuto Shiode (1), Tasuku Nakabori (1), Yoshinobu Saito (1), Naoki Hiramatsu (1), Keisuke Tabata (2), Tsuyoshi Kawabata (2), Maho Hamasaki (2), Hidetoshi Eguchi (3), Hiroaki Nagano (3), Tamotsu Yoshimori (2), Tetsuo Takehara (1)
  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
  2. Department of Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
  3. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
Title Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease
PubMed 27637015
Laboratory Laboratory of Intracellular Membrane Dynamics 〈Prof. Yoshimori〉
Abstract Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It encompasses a spectrum ranging from simple steatosis to fatty liver with hepatocellular injury, termed nonalcoholic steatohepatitis. Recent studies have demonstrated hepatic autophagy being impaired in NAFLD. In the present study, we investigated the impact of Rubicon, a Beclin1-interacting negative regulator for autophagosome-lysosome fusion, in the pathogenesis of NAFLD. In HepG2 cells, BNL-CL2 cells and murine primary hepatocytes, Rubicon was post-transcriptionally upregulated by supplementation with saturated fatty acid palmitate. The upregulation of Rubicon was associated with suppression of the late stage of autophagy as evidenced by accumulation of both LC3-II and p62 expression levels as well as decreased autophagy flux. Its blockade by siRNA attenuated autophagy impairment and reduced palmitate-induced endoplasmic reticulum stress, apoptosis and lipid accumulation. Rubicon was also upregulated in association with autophagy impairment in the livers of mice fed a high-fat diet. Hepatocyte-specific Rubicon knockout mice generated by crossing Rubicon floxed mice with albumin-Cre transgenic mice did not produce any phenotypes on a normal-diet. In contrast, on a high-fat diet, they displayed significant improvement of both liver steatosis and injury as well as attenuation of both ER stress and autophagy impairment in the liver. In human, liver tissues obtained from patients with non-alcoholic fatty liver disease expressed significantly higher levels of Rubicon than those without steatosis.