Arotinoid Acid Introduction Non alcoholic hepatic steatosis
Non-alcoholic hepatic steatosis is characterized by the presence of steatosis in hepatocytes , which leads to the development of fatty liver . It is strongly associated with obesity, insulin resistance, and type II diabetes . They are major risk factors of non-alcoholic hepatic steatosis , which may progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma .
De novo lipogenesis contributes to hepatic steatosis [5,6]. A nuclear receptor, liver X receptor α (LXRα), plays an important role in the regulation of fatty Arotinoid Acid synthesis in hepatocytes through activating sterol regulatory element binding protein 1c (SREBP-1c), a key transcription factor regulating hepatic lipogenesis . The hepatic expression of LXRα and SREBP-1c is increased in patients with steatosis .
Human GPR35, an orphan G protein-coupled receptor, is expressed in lung, stomach, small intestine, colon, spleen, and immune cells in humans [, , , ]. Although several endogenous molecules, such as, cGMP, kynurenic acid, lysophosphatidic acid, and reverse T3, were reported as ligands of GPR35 [10,, , , ], their potencies were subsequently found to be in the micromolar range, which was not supportive of their role as GPR35 ligands .
Recently, the chemokine CXCL17 was reported to be an endogenous ligand of GPR35 , although this was refuted by a later study . However, many synthetic surrogate agonists and antagonists have been identified or developed [, , , , , , , , , ]. Lodoxamide and CID-2745687 have been identified as a potent agonist and a selective antagonist for GPR35 [19,26]. Cromolyn, a mast cell stabilizer was identified as an agonist of GPR35 and was also shown to have antifibrotic effects through its actions on both hepatocytes and hepatic stellate cells [11,30]. Therefore, the function of GPR35 in hepatocytes especially in hepatic steatosis was investigated.
Materials and methods
Acknowledgement This research was supported by a grant from the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology (#2016R1D1A1A009917086).
G protein-coupled receptor 35 (GPR35) is a recently deorphanized cell surface receptor, discovered in 1998 (). It was derived from an open reading frame corresponding to 309 amino acids located in humans on chromosome 2, region q37.3 (). GPR35 belongs to the G protein-coupled receptors (GPCRs) superfamily of integral membrane proteins, which is the largest family of signal transducers, comprised of ∼1000 members (). GPR35 shares homology with subtypes of the purinergic (GPR23/P2Y9), nicotinic acid (HM74), and lysophosphatidylinositol (GPR55) receptors (). The expression analysis of human and rodent GPR35 revealed that it is expressed at different levels in the cells of immune, gastrointestinal, cardiovascular and central nervous systems (; ; ; ). Possible links between GPR35 and a range of pathological conditions including inflammation, asthma, hypertension and diabetes have been proposed (). The data suggest that GPR35 may play an important role in response to hypoxic stress and be a potential target for the treatment of inflammatory, allergic, cardiovascular, and neurological disorders (). Although several endogenous molecules can activate GPR35, none has yet been confirmed as the key endogenous ligand due to lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. However, recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, making them useful as tool compounds (). Kynurenic acid (KYNA), and lysophosphatidic acid have been reported to be GPR35 endogenous ligands (). Niflumic acid, rosmarinic acid, pamoic acid, dicumarol, lodoxamide, nedocromil sodium, cromolyn sodium and zaprinast are well known exogenous GPR35 agonists (; ). Methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID-2745687) and 2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino)benzoic acid (ML-145) are GPR35 antagonists ().