Journal article
Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism
Journal of the American Society of Nephrology, Vol.27(8), pp.2408-2421
08/2016
DOI: 10.1681/ASN.2015060607
PMCID: PMC4978044
PMID: 26712526
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.
Details
- Title: Subtitle
- Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism
- Creators
- Karam Aboudehen - Departments of Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; andMin Soo Kim - Clinical SciencesMatthew Mitsche - Molecular Genetics, andKristina Garland - Molecular Genetics, andNorma Anderson - Molecular Genetics, andLama Noureddine - Departments of Internal MedicineMarco Pontoglio - 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, FranceVishal Patel - Departments of Internal MedicineYang Xie - Clinical SciencesRussell DeBose-Boyd - Molecular Genetics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TexasPeter Igarashi - Departments of Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; and Pediatrics and igarashi@umn.edu
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.27(8), pp.2408-2421
- DOI
- 10.1681/ASN.2015060607
- PMID
- 26712526
- PMCID
- PMC4978044
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Grant note
- P01 HL020948 / NHLBI NIH HHS R01 DK102572 / NIDDK NIH HHS P30 CA142543 / NCI NIH HHS T32 DK007257 / NIDDK NIH HHS P30 DK079328 / NIDDK NIH HHS R37 DK042921 / NIDDK NIH HHS K01 GM109317 / NIGMS NIH HHS
- Language
- English
- Date published
- 08/2016
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094369702771
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