MASH associated lipotoxicity perturbs the expression of hepatic vitamin D bioactivating gene CYP2R1 in humans and mice

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease frequently linked to vitamin D deficiency, which correlates with the severity of the disease and fibrosis. Although reduced dietary intake and sunlight exposure are known contributors, the effect of impaired hepatic vitamin D bioactivation remains unclear. CYP2R1, an enzyme in the liver, converts vitamin D into 25-hydroxyvitamin D (calcifediol), a crucial step in its activation. This study explored the impact of MASH-associated lipotoxicity on CYP2R1 expression and vitamin D metabolism. Analysis of human liver transcriptomic data revealed a significant reduction in CYP2R1 expression in MASH, particularly in advanced fibrosis stages. Similarly, murine models of MASH show decreased hepatic Cyp2r1 expression, elevated liver injury markers, and reduced circulating 25-hydroxyvitamin D levels. Furthermore, in vitro studies demonstrated that palmitic acid caused a dose-dependent decrease in CYP2R1 expression in human hepatocytes, indicating a cell-autonomous effect. Calcifediol significantly induced vitamin D receptor (VDR) expression in human hepatocytes and hepatic stellate cell lines, suggesting the role of intra-hepatic calcifediol in maintaining VDR signalling. These findings uncover lipotoxic repression of CYP2R1 as a previously unrecognized mechanism contributing to vitamin D deficiency and impaired hepatic VDR signalling in MASH, highlighting hepatic vitamin D bioactivation as a potential therapeutic target.