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

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 hepatocyte-specific 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.

Cellular heterogeneity and plasticity during NAFLD progression

“…In other words, if hepatocyte regeneration is impaired by severe liver injury, cholangiocytes contribute to liver regeneration. Studies elucidating the pathogenesis of NAFLD in liver parenchymal cells have been mainly focused on hepatocytes ( Lakhani et al, 2018 ; Lin et al, 2020 ; Lewis et al, 2023 ). However, the functional heterogeneity of cholangiocytes in the development and progression of NAFLD is important and is receiving increasing attention ( Zhou et al, 2021 ; Cadamuro et al, 2022 ).…”

Sodium butyrate alleviates free fatty acid-induced steatosis in primary chicken hepatocytes via the AMPK/PPARα pathway

“…While disorders of hepatic lipid metabolism are characterized by elevated TG levels, increased lipoproteins and cellular steatosis. A multitude of investigators have effectively developed in vitro research models to induce hepatic steatosis by applying an excess of FFA ( Ricchi et al, 2009 ; Lin et al, 2020 ). Our recent study showed that the administration of a blend of FFA, composed of OA and PA in a ratio of 2:1, 1 mmol/L as a concentration, significantly induced steatosis in primary chicken hepatocytes after a 24-h treatment characterized by increased levels of TG, T-CHO, HDL-C, and LDL-C, which consistency with previously studies.…”

Hepatocyte-specific loss of DDB1 attenuates hepatic steatosis but aggravates liver inflammation and fibrosis in MASH

“… 20 HMGB1 is ubiquitously expressed in parenchymal and nonparenchymal hepatic cells, and hepatocytes were proven to be the main hepatic cellular source of HMGB1 in MASH. 18 , 43 It is well known that HMGB1 can promote the conversion of liver macrophages into the proinflammatory M1 phenotype, thus causing an inflammatory response. 44 Moreover, HMGB1 activates HSCs to stimulate liver fibrosis.…”