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Transcription Factor Hepatocyte Nuclear Factor-1beta Regulates Renal Cholesterol Metabolism

Authors
  • Aboudehen, K.
  • Kim, M. S.
  • Mitsche, M.
  • Garland, K.
  • Anderson, N.
  • Noureddine, L.
  • Marco Pontoglio
  • Patel, V.
  • Xie, Y.
  • DeBose-Boyd, R.
  • Igarashi, P.
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology (ASN)
Publication Date
Jul 26, 2016
Volume
27
Issue
8
Pages
21–2408
Identifiers
DOI: 10.1681/asn.2015060607
PMID: 26712526
PMCID: PMC4978044
Source
USPC - SET - SVS
License
Green

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.

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