Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis.

Ting Xiao,Xiuci Liang,Fang Hu,Feng Zhang,Wen Meng,Hailan Liu

doi:10.1530/jme-19-0207

Abstract

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

Highlights

Endoplasmic reticulum (ER) stress due to high fat diet (HFD) feeding or genetic obesity is associated with hepatic steatosis and insulin resistance (Kammoun et al 2009, Yoshiuchi et al 2009, Ye et al 2010, Meng et al 2017, Luo et al 2018)
Recent studies have revealed that ER stress and mitochondrial dysfunction were induced in the liver of HFD-fed mice accompanied by hepatic lipogenesis and steatosis (Hu & Liu 2011, Yecies et al 2011, Ghemrawi et al 2018, Luo et al 2018)
We have confirmed that ER stress is important in the regulation of hepatic lipogenesis, which was consistent with the previous reports about ER stressinduced hepatic steatosis and insulin resistance (Hu & Liu 2011, Yecies et al 2011, Chen et al 2017, Ghemrawi et al 2018, Han & Wang 2018, Luo et al 2018)

Summary

Introduction

Endoplasmic reticulum (ER) stress due to high fat diet (HFD) feeding or genetic obesity is associated with hepatic steatosis and insulin resistance (Kammoun et al 2009, Yoshiuchi et al 2009, Ye et al 2010, Meng et al 2017, Luo et al 2018). Hepatic steatosis is characterized by an excessive accumulation of lipids that leads to disruption of tissue architecture and organ dysfunction. The precise mechanisms by which ER stress causes metabolic disorders and hepatic steatosis are yet to be fully elucidated. Recent studies have revealed that hepatic mTORC1-SREBP1 (sterol regulatory elementbinding protein 1c) signaling plays a key role in regulating systemic hepatic lipid metabolism (Porstmann et al 2008, Düvel et al 2010, Yecies et al 2011, Owen et al 2012, Cai et al 2016). The mechanisms underlying ER stress-induced hepatic lipogenesis and steatosis via the mTORC1- SREBP1 signaling pathway are yet to be completely elucidated

Methods

Results

Conclusion