Clark, A. T.; Russo-Savage, L.; Ashton, L. A.; Haghshenas, N.; Schulman, I. G.

Liver x receptor alpha (LXRalpha, Nr1h3) functions as an important intracellular cholesterol sensor that regulates 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 LXRalpha that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRalpha functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRalpha mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRalpha mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRalpha normally functions to impede the development of liver disease.