LXRalpha Controls Metabolism Associated Steatotic Hepatitis (MASH)

Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates liver fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in hepatic triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease. CRISR was used to generate mice with with mutation of tryptophan (W) 441 of the LXRalpha (Nr1h2) to phenylalanine (F). Liver RNA was isolated from homozygous controls (W/W), heterozygous mutants (W/F), homozygous mutants (F/F) that were maintained on either a normal chow diet or high fat, high cholesterol MASH promoting diet for 4 week. Mice on the high cholesterol diet were treated with daily with the LXR agonist T0901317 or with vehicle for the final 2 week