title: Interaction of ApoA-IV with NR4A1 and NR1D1 Represses G6Pase and PEPCK Transcription: Nuclear Receptor-Mediated Downregulation of Hepatic Gluconeogenesis in Mice and a Human Hepatocyte Cell Line.
abstract: We have previously shown that the nuclear receptor, NR1D1, is a cofactor in ApoA-IV-mediated downregulation of gluconeogenesis. Nuclear receptor, NR4A1, is involved in the transcriptional regulation of various genes involved in inflammation, apoptosis, and glucose metabolism. We investigated whether NR4A1 influences the effect of ApoA-IV on hepatic glucose metabolism. Our in situ proximity ligation assays and coimmunoprecipitation experiments indicated that ApoA-IV colocalized with NR4A1 in human liver (HepG2) and kidney (HEK-293) cell lines. The chromatin immunoprecipitation experiments and luciferase reporter assays indicated that the ApoA-IV and NR4A1 colocalized at the RORα response element of the human G6Pase promoter, reducing its transcriptional activity. Our RNA interference experiments showed that knocking down the expression of NR4A1 in primary mouse hepatocytes treated with ApoA-IV increased the expression of NR1D1, G6Pase, and PEPCK, and that knocking down NR1D1 expression increased the level of NR4A1. We also found that ApoA-IV induced the expression of endogenous NR4A1 in both cultured primary mouse hepatocytes and in the mouse liver, and decreased glucose production in primary mouse hepatocytes. Our findings showed that ApoA-IV colocalizes with NR4A1, which suppresses G6Pase and PEPCK gene expression at the transcriptional level, reducing hepatic glucose output and lowering blood glucose. The ApoA-IV-induced increase in NR4A1 expression in hepatocytes mediates further repression of gluconeogenesis. Our findings suggest that NR1D1 and NR4A1 serve similar or complementary functions in the ApoA-IV-mediated regulation of gluconeogenesis.
authors.affiliation: National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, 157 W 5th Rd, Xincheng, Xi'an, Shaanxi, 710004, China.|Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, 45237-0507, United States of America.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, 45237-0507, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, 45237-0507, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, 45237-0507, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, 45237-0507, United States of America.
authors.forename: W Sean
authors.initials: WS
authors.lastname: DavidsoN
authors.affiliation: National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, 157 W 5th Rd, Xincheng, Xi'an, Shaanxi, 710004, China.
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, 45237-0507, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tso
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000378:metabolism*; D015536:Down-Regulation; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D001054:Apolipoproteins A; C064353:NR1D1 protein, human; C539821:NR4A1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C022205:apolipoprotein A-IV; D005952:Glucose-6-Phosphatase; C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose