title: Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1.
abstract: Besides their role in facilitating lipid absorption, bile acids are increasingly being recognized as signaling molecules that activate cell-signaling receptors. Targeted disruption of the sterol 12α-hydroxylase gene (Cyp8b1) results in complete absence of cholic acid (CA) and its derivatives. Here we investigate the effect of Cyp8b1 deletion on glucose homeostasis. Absence of Cyp8b1 results in improved glucose tolerance, insulin sensitivity, and β-cell function, mediated by absence of CA in Cyp8b1(-/-) mice. In addition, we show that reduced intestinal fat absorption in the absence of biliary CA leads to increased free fatty acids reaching the ileal L cells. This correlates with increased secretion of the incretin hormone GLP-1. GLP-1, in turn, increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1(-/-) mice. Thus, our data elucidate the importance of Cyp8b1 inhibition on the regulation of glucose metabolism.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Achint
authors.initials: A
authors.lastname: Kaur
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Willeke
authors.initials: W
authors.lastname: de Haan
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Piers
authors.initials: P
authors.lastname: Ruddle
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nadeeja
authors.initials: N
authors.lastname: Wijesekara
authors.affiliation: Departments of Pediatrics and Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Departments of Surgery and Pathology and Laboratory Medicine, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.affiliation: A*STAR (Agency for Science, Technology and Research) Institute and Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada mrh@cmmt.ubc.ca.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D019826:Cholic Acid / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D013253:Steroid 12-alpha-Hydroxylase; D019826:Cholic Acid; D005947:Glucose