title: Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.
abstract: HNF-1β is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1β develop kidney cysts, and HNF-1β regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1β-regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression profiling, we identified 1545 protein-coding genes that are directly regulated by HNF-1β in murine kidney epithelial cells. Pathway analysis predicted that HNF-1β regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1β or kidney-specific inactivation of HNF-1β decreased the expression of genes that are essential for cholesterol synthesis, including sterol regulatory element binding factor 2 (Srebf2) and 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr). HNF-1β mutant cells also expressed lower levels of cholesterol biosynthetic intermediates and had a lower rate of cholesterol synthesis than control cells. Additionally, depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1β on the proteins encoded by Srebf2 and Hmgcr, and HNF-1β directly controlled the renal epithelial expression of proprotein convertase subtilisin-like kexin type 9, a key regulator of cholesterol uptake. These findings reveal a novel role of HNF-1β in a transcriptional network that regulates intrarenal cholesterol metabolism.
authors.affiliation: Departments of Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; and.
authors.forename: Karam
authors.initials: K
authors.lastname: Aboudehen
authors.affiliation: Clinical Sciences.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Molecular Genetics, and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitsche
authors.affiliation: Molecular Genetics, and.
authors.forename: Kristina
authors.initials: K
authors.lastname: Garland
authors.affiliation: Molecular Genetics, and.
authors.forename: Norma
authors.initials: N
authors.lastname: Anderson
authors.affiliation: Departments of Internal Medicine.
authors.forename: Lama
authors.initials: L
authors.lastname: Noureddine
authors.affiliation: Department of Development, Reproduction and Cancer, National Institute of Health and Medical Research (INSERM) U1016, The National Center for Scientific Research (CNRS) Joint Research Unit (UMR) 8104, University of Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.affiliation: Departments of Internal Medicine.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.affiliation: Clinical Sciences.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Molecular Genetics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Russell
authors.initials: R
authors.lastname: DeBose-Boyd
authors.affiliation: Departments of Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; and Pediatrics and igarashi@umn.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D051379:Mice
chemical_list: D051539:Hepatocyte Nuclear Factor 1-beta; D002784:Cholesterol
keywords: lipids; polycystic kidney disease; transcription factors