High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)

Abstract

Background: HMGB1 is a proinflammatory cytokine produced in response to tissue injury, but its role in ALD is unknown.Results: HMGB1 increases; translocates; and undergoes acetylation, phosphorylation, and oxidation in ALD. HMGB1 ablation in hepatocytes protects against steatosis and injury in ALD.Conclusion: HMGB1 plays a key role in ALD.Significance: Dissecting how the increase in HMGB1 causes hepatotoxicity is key for understanding the pathogenesis of ALD.

Hepatocyte-specific Hmgb1 Deletion

“…5 In contrast, HMGB1-HC-KO mice are more sensitive to alcohol-induced liver injury due to regulation of fatty acid synthesis and fatty acid b-oxidation, indicating an injurypromoting function of endogenous HMGB1 in the liver. 5 These findings suggest that HMGB1 plays a dual role in the liver during stress. 6 HMGB1 expression in the liver not only protects against ischemia/reperfusion injury, but also increases paracetamol toxicity and alcohol injury.…”

“…4 Dr. Natalia Nieto's lab: "Cell-and organ-specific Hmgb1 ablation was validated by IHC, which confirmed the absence of HMGB1 mostly in hepatocytes and not in other cells or organs such as the kidney." 5 Similarly, in the absence of any treatment, HMGB1-HC-KO mice show normal liver architecture. 5 In contrast, HMGB1-HC-KO mice are more sensitive to alcohol-induced liver injury due to regulation of fatty acid synthesis and fatty acid b-oxidation, indicating an injurypromoting function of endogenous HMGB1 in the liver.…”

“…5 Similarly, in the absence of any treatment, HMGB1-HC-KO mice show normal liver architecture. 5 In contrast, HMGB1-HC-KO mice are more sensitive to alcohol-induced liver injury due to regulation of fatty acid synthesis and fatty acid b-oxidation, indicating an injurypromoting function of endogenous HMGB1 in the liver. 5 These findings suggest that HMGB1 plays a dual role in the liver during stress.…”

Regulation of Posttranslational Modifications of HMGB1 During Immune Responses

“…Interestingly, the oxidative stress, in return, could enhance HMGB1 translocation from the nucleus to the cytoplasm and release, possibly through the keap1/Nrf2 pathway, which is redox regulated and plays a key role in protecting cells against redox stress (21,44,78). Due to the oxidative stress, circulating HMGB1 released by damaged or necrotic hepatocytes during liver injury carries the signature of the posttranslational modifications (5,20). There are several types of serum HMGB1 isoforms, including disulfide-bonded hyperacetylated HMGB1, disulfide-bonded nonacetylated HMGB1, and HMGB1 phosphorylated in serine 35, in liver diseases, such as alcoholic liver disease and drug-induced liver injury (5,20).…”

“…Due to the oxidative stress, circulating HMGB1 released by damaged or necrotic hepatocytes during liver injury carries the signature of the posttranslational modifications (5,20). There are several types of serum HMGB1 isoforms, including disulfide-bonded hyperacetylated HMGB1, disulfide-bonded nonacetylated HMGB1, and HMGB1 phosphorylated in serine 35, in liver diseases, such as alcoholic liver disease and drug-induced liver injury (5,20). Notably, increased total and acetylated HMGB1 in serum were associated with worse prognosis in patients with liver diseases.…”