title: Exendin-4 Inhibits Hepatic Lipogenesis by Increasing β-Catenin Signaling.
abstract: The aim of this study is to investigate whether the beneficial effect of exendin-4 on hepatic steatosis is mediated by β-catenin signaling. After the HepG2 human hepatoma cells were treated with PA for 24 hours, total triglycerides levels were increased in a dose-dependent manner, and the expression levels of perilipin family members were upregulated in cells treated with 400 μM PA. For our in vitro model of hepatic steatosis, HepG2 cells were treated with 400 μM palmitic acid (PA) in the presence or absence of 100 nM exendin-4 for 24 hours. PA increased the expression of lipogenic genes, such as sterol regulatory element-binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) and triglyceride synthesis-involved genes, such as diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2) in HepG2 cells, whereas exendin-4 treatment significantly prevented the upregulation of SREBP-1c, PPARγ, SCD1, FAS, ACC, DGAT1 and DGAT2. Moreover, exendin-4 treatment increased the expression of phosphorylated glycogen synthase kinase-3 beta (GSK-3β) in the cytosolic fraction and the expression of β-catenin and transcription factor 4 (TCF4) in the nuclear fraction. In addition, siRNA-mediated inhibition of β-catenin upregulated the expression of lipogenic transcription factors. The protective effects of exendin-4 on intracellular triglyceride content and total triglyceride levels were not observed in cells treated with the β-catenin inhibitor IWR-1. These data suggest that exendin-4 treatment improves hepatic steatosis by inhibiting lipogenesis via activation of Wnt/β-catenin signaling.
authors.affiliation: Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Gumi, Korea.
authors.forename: Mi Hae
authors.initials: MH
authors.lastname: Seo
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jinmi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Seok-Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Rhee
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Cheol Young
authors.initials: CY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Won-Young
authors.initials: WY
authors.lastname: Lee
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000077270:Exenatide; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007094:Imides / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; D007004:Hypoglycemic Agents; C585534:IWR-1 compound; D007094:Imides; D047495:PPAR gamma; D010455:Peptides; D011804:Quinolines; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D014688:Venoms; D051176:beta Catenin; D019308:Palmitic Acid; D000077270:Exenatide; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; C494881:DGAT1 protein, human; C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D000071679:Glycogen Synthase Kinase 3 beta; D000103:Acetyl-CoA Carboxylase