Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet.

Hikari Okada,Naoto Nagata,Kai Takegoshi,Shuichi Kaneko,Toshinari Takamura,Tetsuro Shimakami,Takuji Tanaka,Mikiko Nakamura,Takayoshi Shirasaki,Riuta Takabatake,Taro Yamashita,Yoshio Sakai,Masao Honda

doi:10.18632/oncotarget.18116

Hikari Okada, Naoto Nagata + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.18116

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Abstract

The pathogenesis of non-alcoholic steatohepatitis (NASH) is still unclear and the prevention of the development of hepatocellular carcinoma (HCC) has not been established. We established an atherogenic and high-fat diet mouse model that develops hepatic steatosis, inflammation, fibrosis, and liver tumors at a high frequency. Using two NASH-HCC mouse models, we showed that peretinoin, an acyclic retinoid, significantly improved liver histology and reduced the incidence of liver tumors. Interestingly, we found that peretinoin induced autophagy in the liver of mice, which was characterized by the increased co-localized expression of microtubule-associated protein light chain 3B-II and lysosome-associated membrane protein 2, and increased autophagosome formation and autophagy flux in the liver. These findings were confirmed using primary mouse hepatocytes. Among representative autophagy pathways, the autophagy related (Atg) 5-Atg12-Atg16L1 pathway was impaired; especially, Atg16L1 was repressed at both the mRNA and protein level. Decreased Atg16L1 mRNA expression was also found in the liver of patients with NASH according to disease progression. Promoter analysis revealed that peretinoin activated the promoter of Atg16L1 by increasing the expression of CCAAT/enhancer-binding-protein-alpha. Interestingly, Atg16L1 overexpression in HepG2 cells inhibited palmitate-induced NF-kB activation and interleukin-6-induced STAT3 activation. We showed that Atg16L1 induced the de-phosphorylation of Gp130, a receptor subunit of interleukin-6 family cytokines, which subsequently repressed phosphorylated-STAT3 (Tyr705) levels, and this process might be independent of autophagy function. Thus, peretinoin prevents the progression of NASH and the development of HCC through activating the autophagy pathway by increased Atg16L1 expression, which is an essential regulator of autophagy and anti-inflammatory proteins.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor outcome
We previously reported the atherogenic and high-fat (Ath+HF) diet-induced nonalcoholic steatohepatitis (NASH) mouse model (Materials and Methods)
To reveal the molecular mechanisms by which peretinoin prevented tumorigenesis in both NASH mouse models, we focused on the status of autophagy

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor outcome. The recent increase in non-alcoholic fatty liver disease (NAFLD) associated with metabolic syndrome could be a strong risk factor for HCC. [2] NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, nonalcoholic steatohepatitis (NASH), which may lead to the accumulation of fibrosis, resulting in cirrhosis and HCC. The pathogenesis of NASH is still unclear and an effective treatment has not been established. The involvement of autophagy in the pathogenesis of NAFLD was first suggested by the finding that autophagy mediates the breakdown of intracellular lipids in hepatocytes. [3] Growing evidence has supported the association of impaired autophagy with the development of NAFLD and progression of NASH. A deficiency of autophagy is involved in tumorigenesis in the liver. A deficiency of autophagy is involved in tumorigenesis in the liver. [4]

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