Hepatic Steatosis

Hepatic Steatosis

Hepatic steatosis, now formally classified under the umbrella of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), is defined as the accumulation of fat in >5% of hepatocytes in the absence of significant alcohol consumption. It is the most common chronic liver condition worldwide, affecting an estimated 25–30% of the global adult population, with prevalence rising sharply among individuals with obesity, type 2 diabetes, and metabolic syndrome. The condition ranges from simple steatosis, which is generally benign, to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), characterized by hepatocyte injury and inflammation that can progress to fibrosis and cirrhosis.

The pathogenesis of hepatic steatosis involves hepatic insulin resistance, increased de novo lipogenesis, impaired fatty acid oxidation, and dysregulated adipose tissue lipolysis that floods the liver with free fatty acids. Glucagon signaling plays a central role in hepatic lipid metabolism by promoting fatty acid oxidation and ketogenesis, and reduced glucagon action in the liver has been implicated in the development of steatosis. This metabolic link makes glucagon receptor agonism a particularly attractive therapeutic strategy for MASLD/MASH.

Retatrutide has demonstrated remarkable liver fat reduction in clinical studies. In the Phase 2 obesity trial, participants receiving the highest dose achieved a mean liver fat reduction of approximately 80–90%, with many reaching complete normalization. These results are driven by both the direct hepatic effects of glucagon receptor agonism—enhanced fatty acid oxidation and reduced lipogenesis—and the indirect benefits of substantial weight loss. Eli Lilly has initiated a dedicated Phase 3 trial evaluating retatrutide specifically for MASH resolution, underscoring the therapeutic potential in this indication.