Endoplasmic Reticulum Stress in Metabolic Disorders

Abstract

Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these diseases has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic disturbance stemmed from over nutrition frequently aggravated by a modern, sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults (Mukherjee, et al., 2015). In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

“…In this study, 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, Ghemrawi et al 2018, Han & Wang 2018, Luo et al 2018). More importantly, we have also shown that ER stress induced mitochondrial stress protein HSP60 expression and impaired mitochondrial function in mouse hepatocytes ( Fig.…”

“…New evidence has emphasized the link between ER and mitochondria during stress response (Zhao et al 2002, Haynes & Ron 2010, Hu & Liu 2011. Mitochondrial stress is induced by calcium and ROS/anti-oxidative signaling in response to ER stress (Hu & Liu 2011, Ghemrawi et al 2018. Consistently, our study showed that ER stress directly induced mitochondrial stress protein HSP60 expression ( Fig.…”

“…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. While ER and mitochondria are subjected to distinct regulations in response to stress, these two organelles are connected at multiple levels during the stress response (Hu & Liu 2011).…”

“…3A). It was reported that insulin sensitivity was regulated by cross-talking between mitochondria and ER during stress (Hu & Liu 2011, Ghemrawi et al 2018. To decide whether overexpression of HSP60 regulates insulin sensitivity, we treated HSP60-overexpressed hepatocytes with or without insulin (Fig.…”

“…Recent studies have showed that mitochondrial stress is associated with mitochondrial dysfunction and metabolic disorders such as hepatic steatosis, insulin resistance, and type 2 diabetes (Venojarvi et al 2008, Hu & Liu 2011, Comert et al 2019, Einer et al 2019. ER and mitochondria have partially overlapping functions, and there is strong crosstalk between the two organelles to regulate hepatic steatosis (Haynes & Ron 2010, Hu & Liu 2011, Ghemrawi et al 2018. However, the cause-and-effect relationship between ER and mitochondrial stress in response to nutrients overloading are yet to be clearly elucidated.…”