UC San Diego

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a prevalent condition characterized by the accumulation of lipids in the liver alongside other metabolic abnormalities. Currently, the intricate pathogenesis of MASLD is not fully understood, and there is no FDA-approved treatment for this disease. One potential therapeutic target for MASLD is the liver X receptors (LXRs) due to their crucial roles in lipid metabolism and inflammation. However, activating hepatic LXRs unfortunately leads to increased hepatic lipid production, making them unsuitable for MASLD treatment in the clinic.

Apart from the liver, LXRs are highly expressed in the intestine with critical roles in cholesterol metabolism, which shows promise in MASLD treatment. However, their role in the intestine is not fully elucidated. Thus, this study aimed to investigate the role of intestinal LXRs by assessing mice with intestinal-specific LXRα/β double knockout (iLXR-DKO) under a high-fat/cholesterol diet (HFCD) that induces MASLD. iLXR-DKO mice exhibited reduced HFCD-induced body weight gain and protection against MASLD development, including diminished hepatic steatosis, hepatocyte injury, and body weight gain. Moreover, iLXR-DKO did not alter food intake or fecal energy output but instead increased energy expenditure, thus further preventing body weight gain and alleviating MASLD symptoms. These findings propose a novel therapeutic strategy in targeting intestinal LXRs for the treatment of MASLD.