Hepatocyte high-mobility group box 1 protects against steatosis and cellular stress during high fat diet feeding
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RESEARCH ARTICLE
Molecular Medicine
Open Access
Hepatocyte high‑mobility group box 1 protects against steatosis and cellular stress during high fat diet feeding Minjie Lin1,2 , Jungke Long2,3, Wenbo Li2,4, Chenxuan Yang2,5, Patricia Loughran2,6, Robert O’Doherty7,8, Timothy R. Billiar2,8, Meihong Deng2,10* and Melanie J. Scott2,8,9*
Abstract Background: Circulating high-mobility group box 1 (HMGB1) plays important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Intracellular HMGB1 is critical for the biology of hepatocytes. However, the intracellular role of HMGB1 in hepatocellular steatosis is unknown. Therefore, we aimed to investigate the role of hepatocytespecific HMGB1 (HC-HMGB1) in development of hepatic steatosis. Methods: Wild type (WT) C57BL/6 and HC-HMGB1−/− mice were fed high-fat diet (HFD) or low-fat diet (LFD) for up to 16 weeks. Results: As expected, HMGB1 translocated from nuclear into cytoplasm and released into circulation after HFD treatment. HC-HMGB1 deficiency significantly reduced circulating HMGB1, suggesting that hepatocyte is a major source of circulating HMGB1 during NAFLD. Unexpectedly, HC-HMGB1 deficiency promoted rapid weight gain with enhanced hepatic fat deposition compared with WT at as early as 4 weeks after HFD treatment. Furthermore, there was no difference between WT and HC-HMGB1−/− mice in glucose tolerance, energy expenditure, liver damage or systemic inflammation. Interestingly, hepatic gene expression related to free fatty acid (FFA) β-oxidation was significantly down-regulated in HC-HMGB1−/− mice compared with WT, and endoplasmic reticulum (ER) stress markers were significantly higher in livers of HC-HMGB1−/− mice. In vitro experiments using primary mouse hepatocytes showed absence of HMGB1 increased FFA-induced intracellular lipid accumulation, accompanied by increased ER-stress, significant downregulation of FFA β-oxidation, and reduced oxidative phosphorylation. Conclusions: Our findings suggest that hepatocyte HMGB1 protects against dysregulated lipid metabolism via maintenance of β-oxidation and prevention of ER stress. This represents a novel mechanism for HMGB1-regulation of hepatocellular steatosis, and suggests that stabilizing HMGB1 in hepatocytes may be effective strategies for prevention and treatment of NAFLD. Keywords: NAFLD, Hepatic steatosis, Liver injury, ER stress, β-Oxidation
*Correspondence: [email protected]; [email protected] 2 Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA Full list of author information is available at the end of the article
Background The global epidemic of nonalcoholic fatty liver disease (NAFLD) poses a drastic threat to public health systems because of its increasing incidence around the world, especially in Western countries. In the United States, NAFLD is one of the most common chronic liver conditions, affecting an estimated 80–100 million individuals
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License
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