Targeting circulating fatty acid-binding protein 4 ameliorates obesity-associated hepatic steatosis

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.

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.

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.

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.

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.