GLS1‐RNA Polymerase II Axis Mediates Glutamine‐Dependent Hepatoprotective Effects on Alcoholic Liver Disease in High‐Protein Diets

Abstract The RNA polymerase II (RNA pol II) complex is essential for gene transcription throughout life, and numerous cofactors have been identified as critical for diverse transcriptional processes. Herein, it is discovered that the RNA pol II complex is modulated by glutaminase 1 (GLS1), which affects lipid metabolism. In alcoholic fatty liver disease (AFLD), RNA pol II activation is observed, whereas RNA pol II inhibition reverse hepatic steatosis. Furthermore, high‐protein diets are recognized for their adjuvant effect on patients with AFLD; glutamine is indispensable for its protective effects against hepatic steatosis, which is dependent on RNA pol II. Mechanistically, GLS1 acts as a chaperone that affects the RNA pol II complex in the nucleus by interacting with its subunits, POLR2H and POLR2E. In vivo studies have shown that hepatic overexpression of GLS1 ameliorates alcohol‐induced fatty liver, whereas deficiency worsens this condition. Moreover, the overexpression of POLR2E or POLR2H, but not the truncated variants, abolishes the protective effects of GLS1 against alcohol‐induced fatty liver. Thus, the study clarifies GLS1 as a cofactor involved in assembling the RNA pol II complex, regulating hepatic steatosis, and provides foundational insights for future therapeutic approaches in AFLD.