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).…”

Regulatory Networks, Management Approaches, and Emerging Treatments of Nonalcoholic Fatty Liver Disease

“…Studies have shown that HMGB1 is elevated in NAFLD patients and that it accelerates liver damage and inflammation in the early stages of NAFLD [24]. Deletion of HMGB1 in hepatocytes increases early body weight gain and lipid accumulation in mice and increases ER stress in liver and hepatocytes to promote liver injury during NAFLD [25]. Inhibition of HMGB1 release from hepatocytes attenuates liver damage [26].…”

Modulación de la microbiota intestinal en el tratamiento de la enfermedad de hígado graso no alcohólico y síndrome metabólico. Estudio de un tratamiento experimental con quercetina y de la transferencia de microbiota a ratones libres de gérmenes = Intestinal microbiota modulation in the treatment of non-alcoholic fatty liver disease and metabolic syndrome. Study of an experimental treatment with quercetin and intestinal microbiota transfer to germ-free mice

“…A nivel hepático la alimentación con la dieta rica en grasa provocó en los ratones C57BL/6J la acumulación intrahepática de lípidos con principio de degeneración balonizante y focos de inflamación compatible con el desarrollo de NAFLD, pero sin llegar a la aparición de fibrosis propia de la fase de esteatohepatitis, tal y como se recoge habitualmente en modelos experimentales murinos que emplean la misma dieta en periodos análogos (Amato et al, 2017;Wang et al, 2019;Lin et al, 2020). Junto a los hallazgos histológicos una mayor concentración de triglicéridos y, muy especialmente, de ácidos grasos libres fueron las principales evidencias de un marcado desarrollo de esteatosis no alcohólica en los ratones alimentados con la dieta rica en grasa.…”