Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2α-ATF4 pathway

Abstract

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2α)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation.

Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK

“…Sesn2 has been verified to directly bind and function upstream of AMPK (7,10,34,35), which was also confirmed in the present study (Fig. 7I).…”

Carbon monoxide-induced TFEB nuclear translocation enhances mitophagy/mitochondrial biogenesis in hepatocytes and ameliorates inflammatory liver injury

“…Although the roles of TFEB in autophagy and lysosomal biogenesis has been well-clarified 30 , the identification of molecules that can regulate TFEB remain largely unknown. Previously, our study showed that CO activates PERK signaling through generation of mtROS 31 . In this study, we show that a mild increase in mtROS levels in response to CO treatment leads to PERK activation, Ca 2+ release, and calcineurin-dependent TFEB nuclear translocation (Figs.…”

Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein

“…It is vital in the pathological process of inflammation and sepsis 41 , and appears to be one of the lethal contributors to immune dysfunction and lymphocyte apoptosis 42 . It has been demonstrated that the upregulation of SESN2 is uniquely induced under ERS response 43 . Conversely, SESN2 exerts a marked influence on the response of ERS.…”