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

9 Scopus citations

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 2016

ASJC Scopus subject areas

  • Nephrology

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