Transcription factor hepatocyte nuclear factor-1β regulates renal cholesterol metabolism

Karam Aboudehen, Min Soo Kim, Matthew Mitsche, Kristina Garland, Norma Anderson, Lama Noureddine, Marco Pontoglio, Vishal Patel, Yang Xie, Russell Debose-Boyd, Peter Igarashi

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 culturemediummitigated the inhibitory effects ofmutant HNF-1β on the proteins encoded by Srebf2 andHmgcr, andHNF-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.

Original languageEnglish (US)
Pages (from-to)2408-2421
Number of pages14
JournalJournal of the American Society of Nephrology
Volume27
Issue number8
DOIs
StatePublished - Aug 1 2016

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Hepatocyte Nuclear Factor 1
Cholesterol
Kidney
Sterols
Hydroxymethylglutaryl CoA Reductases
Gene Regulatory Networks
Chromatin Immunoprecipitation
Essential Genes
Gene Expression Profiling
transcription factor nuclear factor 1
Genes
Cysts
Transcription Factors
Epithelial Cells
Gene Expression
Mutation

ASJC Scopus subject areas

  • Nephrology

Cite this

Transcription factor hepatocyte nuclear factor-1β regulates renal cholesterol metabolism. / Aboudehen, Karam; Kim, Min Soo; Mitsche, Matthew; Garland, Kristina; Anderson, Norma; Noureddine, Lama; Pontoglio, Marco; Patel, Vishal; Xie, Yang; Debose-Boyd, Russell; Igarashi, Peter.

In: Journal of the American Society of Nephrology, Vol. 27, No. 8, 01.08.2016, p. 2408-2421.

Research output: Contribution to journalArticle

Aboudehen, Karam ; Kim, Min Soo ; Mitsche, Matthew ; Garland, Kristina ; Anderson, Norma ; Noureddine, Lama ; Pontoglio, Marco ; Patel, Vishal ; Xie, Yang ; Debose-Boyd, Russell ; Igarashi, Peter. / Transcription factor hepatocyte nuclear factor-1β regulates renal cholesterol metabolism. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 8. pp. 2408-2421.
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