title: Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway.
abstract: Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Horng-Yih
authors.initials: HY
authors.lastname: Ou
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hung-Tsung
authors.initials: HT
authors.lastname: Wu
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Feng-Hwa
authors.initials: FH
authors.lastname: Lu
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Chu
authors.initials: YC
authors.lastname: Su
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hao-Chang
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jin-Shang
authors.initials: JS
authors.lastname: Wu
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chao-Liang
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan Division of Endocrinology and MetabolismDepartment of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanResearch Center of Herbal MedicineNew Drugs, and Nutritional Supplements, National Cheng Kung University, Tainan, TaiwanDepartment of Family MedicineNational Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, TaiwanCollege of MedicineInstitute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan changcj.ncku@gmail.com.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004963:Estrenes / Q000008:administration & dosage / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004963:Estrenes; C473034:FFAR1 protein, human; D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; D051780:Sterol Regulatory Element Binding Protein 1; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D054801:Phosphoinositide Phospholipase C
keywords: free fatty acid receptor 1; hepatic steatosis; insulin resistance; p38-MAPK; sterol regulatory element-binding protein