title: Apolipoprotein A-IV reduces hepatic gluconeogenesis through nuclear receptor NR1D1.
abstract: We showed recently that apoA-IV improves glucose homeostasis by enhancing pancreatic insulin secretion in the presence of elevated levels of glucose. Therefore, examined whether apolipoprotein A-IV (apoA-IV) also regulates glucose metabolism through the suppression of hepatic gluconeogenesis. The ability of apoA-IV to lower gluconeogenic gene expression and glucose production was measured in apoA-IV(-/-) and wild-type mice and primary mouse hepatocytes. The transcriptional regulation of Glc-6-Pase and phosphoenolpyruvate carboxykinase (PEPCK) by apoA-IV was determined by luciferase activity assay. Using bacterial two-hybrid library screening, NR1D1 was identified as a putative apoA-IV-binding protein. The colocalization and interaction between apoA-IV and NR1D1 were confirmed by immunofluorescence, in situ proximity ligation assay, and coimmunoprecipitation. Enhanced recruitment of NR1D1 and activity by apoA-IV to Glc-6-Pase promoter was verified with ChIP and a luciferase assay. Down-regulation of apoA-IV on gluconeogenic genes is mediated through NR1D1, as illustrated in cells with NR1D1 knockdown by siRNA. We found that apoA-IV suppresses the expression of PEPCK and Glc-6-Pase in hepatocytes; decreases hepatic glucose production; binds and activates nuclear receptor NR1D1 and stimulates NR1D1 expression; in cells lacking NR1D1, fails to inhibit PEPCK and Glc-6-Pase gene expression; and stimulates higher hepatic glucose production and higher gluconeogenic gene expression in apoA-IV(-/-) mice. We conclude that apoA-IV inhibits hepatic gluconeogenesis by decreasing Glc-6-Pase and PEPCK gene expression through NR1D1. This novel regulatory pathway connects an influx of energy as fat from the gut (and subsequent apoA-IV secretion) with inhibition of hepatic glucose production.
authors: From the Cincinnati Obesity Research Center, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio 45237 and.
authors: Xiaoming
authors: X
authors: Li
authors: Min
authors: M
authors: Xu
authors: Fei
authors: F
authors: Wang
authors: Alison B
authors: AB
authors: Kohan
authors: Michael K
authors: MK
authors: Haas
authors: Qing
authors: Q
authors: Yang
authors: Danwen
authors: D
authors: Lou
authors: Silvana
authors: S
authors: Obici
authors: W Sean
authors: WS
authors: Davidson
authors: Patrick
authors: P
authors: Tso
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis* / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology
chemical_list: D001054:Apolipoproteins A; C064353:NR1D1 protein, human; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C022205:apolipoprotein A-IV; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose
keywords: Apolipoprotein A-IV; Apolipoproteins; Diabetes; Gluconeogenesis; NR1D1; Nuclear Receptors; Phosphoenolpyruvate Carboxykinase