Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation.

Qinglan Wang,Jeong Han Kim,Roberta A Gottlieb,I-Fang Hsin,Ping Liu,Ekihiro Seki,Mitsuru Naiki,Wei Tu,Zhijun Wang,Aleksandr Stotland,Mingyi Xu

doi:10.3389/fphys.2020.00950

Abstract

The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitate-and linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK.

Highlights

The prevalence of non-alcoholic fatty liver disease (NAFLD) has dramatically increased in the last decade, and NAFLD has become one of the most common health concerns associated with metabolic syndrome, affecting 25% of the adult populations in Western and Asian countries (Fan et al, 2017; Friedman et al, 2018)
PA and LA treatments increased the TG content in primary hepatocytes, whereas NTP treatment significantly decreased PA- and LAinduced increases in TG content (Figure 1C). These findings demonstrate that NTP inhibits lipid accumulation in hepatocytes
Because AMPK induces the expression of PGC-1β, which regulates lipid homeostasis and mitochondrial biogenesis (Villena, 2015), we examined whether PGC-1β plays a role in the NTPmediated anti-steatotic effect

Summary

Introduction

The prevalence of non-alcoholic fatty liver disease (NAFLD) has dramatically increased in the last decade, and NAFLD has become one of the most common health concerns associated with metabolic syndrome, affecting 25% of the adult populations in Western and Asian countries (Fan et al, 2017; Friedman et al, 2018). The disease spectrum of NAFLD ranges from simple steatosis to steatosis with hepatocyte ballooning, liver inflammation, and fibrosis, referred to as non-alcoholic steatohepatitis (NASH). 20–25% of NAFLD patients develop NASH, which may progress to fibrosis and cirrhosis (Friedman et al, 2018; Younossi et al, 2018). The goal of the present study was to investigate the potential to repurpose the drug Neurotropin (NTP) for the treatment of NAFLD through the in vitro model

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Conclusion