Hepatic Fat
Definition
The amount of triglyceride stored within liver cells, often measured by imaging techniques such as MRI-PDFF, which serves as an important marker of metabolic liver disease and insulin resistance.
Hepatic Fat
Hepatic fat, also referred to as intrahepatic triglyceride content, represents the accumulation of lipid droplets within hepatocytes. Under normal physiological conditions, the liver contains less than 5% fat by weight. When hepatic fat content exceeds this threshold, the condition is classified as hepatic steatosis, the hallmark feature of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease or NAFLD). Hepatic fat accumulation results from an imbalance between lipid influx (from circulating free fatty acids, de novo lipogenesis, and dietary sources) and lipid disposal (through beta-oxidation and very-low-density lipoprotein secretion). Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) has emerged as the gold standard non-invasive quantitative measure of hepatic fat, offering high sensitivity and reproducibility for detecting changes in liver fat content in clinical trials.
Elevated hepatic fat is strongly associated with insulin resistance and serves as both a consequence and a driver of metabolic dysregulation. Intrahepatic lipid accumulation impairs insulin signaling in hepatocytes, leading to inadequate suppression of hepatic glucose production and contributing to systemic hyperglycemia. Furthermore, hepatic steatosis can progress to steatohepatitis (MASH), characterized by hepatocyte injury, inflammation, and fibrosis, which may ultimately lead to cirrhosis and hepatocellular carcinoma. The prevalence of MASLD is estimated at 25-30% of the global adult population and is substantially higher among individuals with obesity and type 2 diabetes.
Clinical Relevance to Retatrutide
Retatrutide has shown remarkable efficacy in reducing hepatic fat content in clinical studies. The glucagon receptor agonism component of retatrutide is particularly relevant, as glucagon signaling in the liver directly promotes fatty-acid oxidation and suppresses de novo lipogenesis, mechanisms that directly target the pathophysiology of hepatic fat accumulation. In phase 2 trials, participants treated with retatrutide demonstrated substantial reductions in hepatic fat as measured by MRI-PDFF, with many achieving normalization of liver fat content (below the 5% threshold). These findings have generated considerable interest in retatrutide as a potential therapeutic agent for MASLD and MASH, and dedicated studies evaluating its effects on liver histology are underway.