Targeting Circulating FABP4 Ameliorates Obesity-Associated Hepatic Steatosis

Abstract

Obesity is a major driver of hepatic steatosis, yet the molecular link between excess adiposity and hepatocellular lipid accumulation remains incompletely defined. Here, we identify circulating fatty acid-binding protein 4 (FABP4) as a key mediator of adipocyte-hepatocyte lipid crosstalk in obesity. Analyses of human liver specimens and mouse models reveal aberrant accumulation of FABP4 protein--but not transcript--in hepatocytes during steatosis, indicating an extrinsic source. Genetic deletion of FABP4, specifically in adipocytes, protects against high fat diet-induced hepatic steatosis without altering obesity or systemic lipid levels. Mechanistically, circulating FABP4 directly binds to hepatocytes, facilitating free fatty acid uptake. Furthermore, we developed a high-affinity humanized monoclonal antibody that selectively neutralizes circulating FABP4, blocks hepatocyte binding, suppresses fatty acid uptake, and markedly attenuates hepatic steatosis in multiple obese mouse models. These findings establish circulating FABP4 as a pathogenic lipid chaperone and a promising therapeutic target for obesity-associated hepatic steatosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/701451v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@5b91d5org.highwire.dtl.DTLVardef@1c34892org.highwire.dtl.DTLVardef@1d17ea9org.highwire.dtl.DTLVardef@d2b43c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHepatocytic accumulation of extrinsic FABP4 links adiposity to liver lipid deposition. C_LIO_LISpecific deletion of FABP4 in adipocytes prevents hepatic steatosis without affecting systemic lipid levels or obesity. C_LIO_LICirculating FABP4 derived from adipocytes directly binds hepatocytes to facilitate free fatty acid transfer. C_LIO_LIBlocking circulating FABP4 with a high-affinity anti-FABP4 monoclonal antibody inhibits hepatocyte lipid uptake and attenuates steatosis in multiple obese mouse models. C_LI