Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism

• Published in: Journal of hepatology Vol. 75; no. 2; pp. 400 - 413
• Main Authors: Li, Jie, Zhu, Xiaoyun, Zhang, Meihui, Zhang, Yanqiu, Ye, Shengtao, Leng, Yingrong, Yang, Ting, Kong, Lingyi, Zhang, Hao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2021; Elsevier Science Ltd
• Subjects: Acids; Animal models; Animals; Bile; Bile Acids and Salts - metabolism; Bile ducts; Cholangitis; Cholestasis; Cholestatic liver disease; Cholic acid; Chromatin; Disease Models, Animal; DNA microarrays; EGR-1; EGR-1 protein; Gallbladder diseases; Gene regulation; Hepatocytes; Homeostasis; Immunoprecipitation; Jaundice, Obstructive - etiology; Jaundice, Obstructive - genetics; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Biliary - complications; Liver diseases; LIX1L; LRH-1; Mice; MicroRNAs; miRNA; Patients; Post-transcription; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Therapeutic targets; EGR-1; LRH-1; Cholestatic liver disease; MicroRNAs; LIX1L
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2021.02.035

Cholestatic liver diseases comprise a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury. Regulation of bile acid (BA) synthesis and homeostasis is a promising strategy for the treatment of cholestatic liver disease. Limb expression 1-like protein (LIX1L) plays an important role in post-transcriptional gene regulation, yet its role in cholestatic liver injury remains unclear. LIX1L expression was studied in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), and 3 murine models of cholestasis (bile duct ligation [BDL], Mdr2 knockout [Mdr2-/-], and cholic acid [CA] feeding). Lix1l knockout mice were employed to investigate the function of LIX1L in cholestatic liver diseases. Chromatin immunoprecipitation assays were performed to determine whether Egr-1 bound to the Lix1l promoter. MiRNA expression profiling was analyzed by microarray. An adeno-associated virus (AAV)-mediated hepatic delivery system was used to identify the function of miR-191-3p in vivo. LIX1L expression was increased in the livers of patients with PSC and PBC, and in the 3 murine models, as well as in BA-stimulated primary mouse hepatocytes. BA-induced Lix1l upregulation was dependent on Egr-1, which served as a transcriptional activator. LIX1L deficiency attenuated cholestatic liver injury in BDL and Mdr2-/- mice. MiR-191-3p was the most reduced miRNA in livers of WT-BDL mice, while it was restored in Lix1l-/--BDL mice. MiR-191-3p targets and downregulates Lrh-1, thereby inhibiting Cyp7a1 and Cyp8b1 expression. AAV-mediated hepatic delivery of miR-191-3p significantly attenuated cholestatic liver injury in Mdr2-/- mice. LIX1L deficiency alleviates cholestatic liver injury by inhibiting BA synthesis. LIX1L functions as a nexus linking BA/Egr-1 and miR-191-3p/LRH-1 signaling. LIX1L and miR-191-3p may be promising targets for the treatment of BA-associated hepatobiliary diseases. Bile acid homeostasis can be impaired in cholestatic liver diseases. Our study identified a novel mechanism of positive feedback regulation in cholestasis. LIX1L and miR-191-3p represent potential therapeutic targets for cholestatic liver diseases. [Display omitted] •LIX1L was upregulated in cholestatic liver specimens from both patients and mouse models.•Bile acids triggered upregulation of Egr-1, which induced LIX1L expression.•LIX1L deficiency alleviated cholestatic liver injury by inhibiting bile acid synthesis.•Overexpression of miR-191-3p using AAV protected against cholestatic liver injury in mouse models.