Targeting Circulating Fatty Acid Binding Protein 4 Ameliorates Obesity-Associated Hepatic Steatosis.

BACKGROUND & AIMS: Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular mechanisms linking excess adiposity to hepatocellular lipid accumulation remain incompletely defined. We investigated whether circulating fatty acid-binding protein 4 (FABP4) mediates adipocyte-hepatocyte lipid crosstalk in obesity. METHODS: FABP4 expression and localization were analyzed in human liver specimens (n=55) and multiple mouse models of hepatic steatosis. Whole-body and tissue-specific Fabp4 knockout mice (n=7-10/group) were subjected to high-fat diet feeding and assessed for hepatic steatosis. Hepatocyte fatty acid uptake assays were performed in vitro. A high affinity humanized monoclonal antibody targeting FABP4 was generated and evaluated for its effects on hepatocyte binding, lipid uptake, and hepatic steatosis in obese mouse models. RESULTS: FABP4 protein, but not mRNA, was markedly increased in hepatocytes from steatotic human livers (p<0.05) and obese mice (p<0.0001), suggesting an extrinsic source. Adipocyte-specific deletion of Fabp4 protected mice from diet-induced hepatic steatosis without affecting body weight or circulating lipid levels (p<0.01). Mechanistically, circulating FABP4 directly bound to hepatocytes and facilitated free fatty acid uptake. Neutralization of circulating FABP4 with a humanized monoclonal antibody blocked hepatocyte binding (p<0.001), reduced fatty acid uptake (p<0.01), and significantly attenuated hepatic steatosis across multiple obese mouse models. CONCLUSIONS: These findings identify circulating FABP4 as a pathogenic lipid chaperone that links adipose tissue dysfunction to hepatocellular lipid accumulation. Targeting circulating FABP4 represents a promising strategy for prevention and treatment of obesity-associated hepatic steatosis. IMPACT AND IMPLICATIONS: This study identifies circulating FABP4 as an endocrine lipid chaperone that mediates pathogenic adipose-liver crosstalk in obesity by directly promoting hepatocellular fatty acid uptake. The accumulation of FABP4 protein in hepatocytes in the absence of transcriptional induction reveals a previously unrecognized mechanism driving hepatic steatosis independently of systemic lipid levels. Importantly, neutralization of circulating FABP4 markedly attenuates steatosis in obese mouse models, establishing FABP4 as a tractable therapeutic target and supporting adipose-derived lipid carriers as a new intervention axis for MASLD.