Ubiquitin-specific protease 22 ameliorates chronic alcohol-associated liver disease by regulating BRD4. (June 2021)

• Record Type: Journal Article
• Authors: Yan, Ran; Chu, Junyi; Zhou, Yuanzhang; Shan, Wen; Hu, Yan; Lin, Musen; Zhao, Yan; Sun, Ruimin; Wang, Zhecheng; Lv, Li; Wang, Liming; Yao, Jihong; Zhang, Ning
• Is Part Of: Pharmacological research. Volume 168(2021)
• Publication Date: 2021-06
• Subjects: ALD alcohol-associated liver disease -- USP ubiquitin-specific protease -- DUB deubiquitinating enzymes -- HCC hepatocellular carcinoma -- SIRT1 sirtuin 1 -- BET bromo and extra-terminal -- BRD4 bromodomain-containing protein 4 -- SPOP speckle-type POZ protein -- LV lentiviral -- EtOH ethanol -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- TC total cholesterol -- TG triglyceride -- H&E hematoxylin-eosin staining -- THE transmission electron microscopy -- IL interleukin -- CYP2E1 cytochrome P450 2E1; Ubiquitin-specific protease -- Alcohol-associated liver disease -- Inflammation -- Deubiquitination -- BRD4; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105594
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Alcohol-associated liver disease (ALD) is a liver system disease caused by alcohol abuse, and it involves complex processes ranging from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma. Steatosis and inflammation are the main phenomena involved in ALD. Ubiquitin-specific protease 22 (USP22) plays an important role in liver steatosis; however, its functional contribution to ALD remains unclear. USP22-silenced mice were fed a Lieber-DeCarli liquid diet. AML-12 and HEK293T cells were used to detect the interaction between USP22 and BRD4. Here, we report that hepatic USP22 expression was dramatically upregulated in mice with ALD. Inflammation and steatosis were significantly ameliorated following USP22 silencing in vivo, as indicated by decreased IL-6 and IL-1β levels. We further showed that the overexpression of USP22 increased inflammation, while knocking down BRD4 suppressed the inflammatory response in AML-12 cells. Notably, USP22 functioned as a BRD4 deubiquitinase to facilitate BRD4 inflammatory functions. More importantly, the expression levels of USP22 and BRD4 in patients with ALD were significantly increased. In conclusion, USP22 acts a key pathogenic factor in ALD by deubiquitinating BRD4, which facilitates the inflammatory response and aggravates ALD. Graphical Abstract: ga1