Vitamin D Suppresses Hepatic Stellate Cell Activation by Negatively Regulating Glutamine/β-Catenin Metabolism

Background: Liver fibrosis is a serious health problem that may lead to a lot of liver diseases, such as liver cirrhosis and hepatocellular carcinoma. Liver fibrosis are composed mainly by activated hepatic stellate cells (HSCs). Methods: To explore the effects of vitamin D in HSC activation and assess the relationships between vitamin D and glutamine metabolism in HSC activation and liver fibrosis in mice. We extracted HSCs from C57BL/6J mice which were activated by glutamine and glucose for 7 days with or without inhibitors or vitamin D. The expression of HSC activation related proteins, HSC proliferation, the acetylation of β-catenin, and the metabolites were measured by western blot or commercial kits. Findings: Glutamine activated HSCs and promoted the expression of alpha smooth muscle actin (α-SMA), glutaminase-1 (GLS1), Adenosine triphosphate (ATP), citrate lyase (ACLY), citrate, acetyl-coenzyme (Ac-CoA), adenosine triphosphate (ATP) and, lactic acid (Lac), and promoted β-catenin acetylation. however, glucose may reverse the phenomenon. The inhibitors of GLS1 and ACLY also reached the same conclusions with glutamine. In vitro, vitamin D depressed the HSC activation and cell viability by inhibiting glutamine metabolism, and reduced β-catenin acetylation. In vivo, vitamin D significantly inhibited liver fibrosis levels, β-catenin acetylation, and glutamine metabolites. Interpretation: Vitamin D suppressed HSC activation and alleviated mouse liver fibrosis by inhibiting the Gln/β-catenin metabolism. Funding: This study was funded by the National Natural Science Foundation of China Program (Grant No. 81872672). Declaration of Interest: None to declare. Ethical Approval: All animal experiments were in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animal with approval of the First Affiliated Hospital at Zhejiang University School of Medicine, Hangzhou.