Hepatocyte high-mobility group box 1 protects against steatosis and cellular stress during high fat diet feeding

Minjie Lin,Patricia Loughran,Chenxuan Yang,Melanie J Scott,Meihong Deng,Timothy R Billiar,Robert O'Doherty,Jungke Long,Wenbo Li

doi:10.1186/s10020-020-00227-6

Abstract

BackgroundCirculating 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 hepatocyte-specific HMGB1 (HC-HMGB1) in development of hepatic steatosis.MethodsWild type (WT) C57BL/6 and HC-HMGB1−/− mice were fed high-fat diet (HFD) or low-fat diet (LFD) for up to 16 weeks.ResultsAs 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.ConclusionsOur 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.

Highlights

Circulating high-mobility group box 1 (HMGB1) plays important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)
high-fat diet (HFD) triggers HMGB1 loss in hepatocytes and increases serum HMGB1 level Extracellular HMGB1 has been identified as a mediator of HFD-induced liver damage and inflammation during the early stages of NAFLD (Li et al 2011)
In Wild type (WT) mice as early as 2 weeks of HFD there was significant movement of HMGB1 into the cytoplasm and intercellular space of hepatocytes and this increased in a time-dependent manner

Summary

Introduction

Circulating high-mobility group box 1 (HMGB1) plays important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intracellular role of HMGB1 in hepatocellular steatosis is unknown. 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. High-mobility group box 1 (HMGB1) is a highly conserved, ubiquitous nuclear protein constitutively expressed in most cell types (Klune et al 2008). In response to cellular stress HMGB1 is mobilized from the nucleus into the cytoplasm, where it can influence intracellular processes such as autophagy. HMGB1 can be actively and passively released from cells where it can act as a pro-inflammatory damageassociated molecular pattern (DAMP) (Jingjing et al 2015)

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