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Free Radic Biol Med. 2017 Sep;110:81-91. doi: 10.1016/j.freeradbiomed.2017.05.026. Epub 2017 May 31.

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

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Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, NY, USA.
National Creative Research Laboratory for Ca(2+) Signaling Network, Chonbuk National University, Medical School, Jeonju, Republic of Korea. Electronic address:
Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea. Electronic address:


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.


Autophagy; Carbon monoxide; Endoplasmic reticulum stress; Hepatic steatosis

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