Grant: Project Grant

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition characterized by the accumulation of excess fat in the liver, observed in individuals without a history of alcohol abuse. Recognized as a significant component of the global obesity epidemic, MASLD affects an estimated 5 to 20% of the general population, with a higher prevalence of up to 75% among patients with obesity and type 2 diabetes (T2D). Patients with MASLD have no symptoms or signs early on, leading to its reputation as a "silent killer" until the disease has progressed to a more severe stage, like metabolic-associated steatohepatitis (MASH). MASH is characterized by liver fat accumulation and inflammation and can progress to liver failure. Currently, there are no FDA-approved therapies exclusively designed for treating MASLD and MASH, leaving lifestyle modifications as the sole treatment option for affected individuals. Consequently, there is an urgent need to identify effective agents to reduce liver fat accumulation in MASLD and MASH patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a promising class of glucose-lowering drugs for managing these conditions. Both preclinical and clinical studies have demonstrated that SGLT2 inhibitors not only reduce liver fat accumulation but also improve serum markers of liver injury in patients with or without T2D. These positive effects suggest that the mechanisms behind SGLT2 inhibitors' hepatoprotective actions extend beyond blood glucose reduction. This proposal aims to investigate how SGLT2 inhibitors alleviate liver fat accumulation and inflammation in MASLD and MASH animal models, with the hope that uncovering the underlying mechanisms will pave the way for novel treatment approaches in addressing these liver conditions.