261-LB: Hepatocyte Gdf15 Protects against CCL4-Induced Liver Injury Independent of Changes in Feeding and Inflammation

Abstract

Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels increase in obesity and fibrotic liver disease, like NAFLD. GDF15 KO mice develop more severe fibrosis after carbon tetrachloride (CCL4) treatment, suggesting a protective effect of GDF15. Despite this, the tissue specific sites of GDF15 production during liver injury are unknown and the potential for local action is understudied. To determine the hepatocyte specific contribution of Gdf15 to changes in circulating GDF15 and effects on fibrosis, we utilized a Gdf15 KO-first mouse strain where endogenous expression of Gdf15 can be restored in a tissue specific fashion via Flp recombinase (FLP). Gdf15 KO-first mice received AAV8-TBG-Gfp (KO+GFP) or AAV8-TBG-Flp (liver specific Gdf15 expression; KO+FLP) and were treated with CCL4 3X per week for 3 weeks alongside wild type (WT) controls. CCL4 increased circulating GDF15 7X in WT and 3.5X in KO+FLP compared with WT vehicle (VEH), and levels were undetected in KO+GFP mice. CCL4 caused significant BW loss in WT and KO+FLP mice and had no effect on KO+GFP mice. CCL4 reduced feeding similarly in all groups despite marked differences in circulating GDF15. Liver gene expression markers of fibrosis were upregulated in KO+GFP mice compared with WT and KO+FLP mice. Interestingly, despite differences in fibrosis, circulating cytokines and liver expression of inflammatory markers were reduced in KO+GFP and KO+FLP compared with WT mice. These data demonstrate that hepatocyte Gdf15 protects against CCL4-induced fibrotic liver injury independent of feeding and inflammation. They also suggest that GDF15 may have local, GFRAL-independent effects within liver to remodel the extracellular matrix that require further study. Disclosure J. Kastroll: None. M. J. Jurczak: None. F. Bello: None. A. Vandevender: None. I. J. Sipula: None. J. Alder: None.