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Lodoxamide protects against LXR‐mediated steatosis through G protein‐coupled receptor 35 in Hep3B cells and primary mouse hepatocytes
Author(s) -
Nam SoYeon,
Im Dongsoon
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.563.6
Subject(s) - steatosis , hepatocyte , biology , hepatic stellate cell , receptor , microbiology and biotechnology , biochemistry , endocrinology , in vitro
Background G protein‐coupled receptor 35 has been an orphan receptor, although synthetic agonists and antagonists have been developed. Cromolyn and lodoxamide, mast cell stabilizers, were reported as agonists. Recently, cromolyn exhibited antifibrotic effects through actions on hepatocytes and stellate cells. However, the function of GPR35 in hepatocytes has not been investigated. METHODS Using an in vitro model of liver X receptor (LXR)‐mediated hepatocellular steatosis, the roles of lodoxamide and GPR35 were investigated in human and mouse hepatocytes. RESULTS T0901317, a specific LXR activator, induced lipid accumulation in Hep3B human hepatoma cells. This lipid accumulation was inhibited by lodoxamide, the most potent agonist of GPR35. The protective effects of lodoxamide were inhibited by CID2745687, a specific GPR35 antagonist or by siRNA trnasfection. T0901317 treatment induced expression of SREBP‐1c, a key transcription factor for lipid synthesis. Lodoxamide inhibited the induction of SREBP‐1c proteins in a GPR35‐dependent manner. Using specific inhibitors of cellular signaling components, lodoxamide‐induced inhibition of lipid accumulation was found to be mediated through p38 MAPKs and JNK, but not through Gi/o proteins, PI3K, and ERKs. Furthermore, the protective effect of lodoxamide was confirmed in mouse primary hepatocytes. CONCLUSION Therefore, the present data suggest that GPR35 may function to protect against lipid accumulation in the liver. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .