Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.

Citation data:

Journal of the American Society of Nephrology : JASN, ISSN: 1533-3450, Vol: 27, Issue: 8, Page: 2408-21

Publication Year:
2016
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Link-outs 8
Citations 3
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PMID:
26712526
DOI:
10.1681/asn.2015060607
PMCID:
PMC4978044
Author(s):
Aboudehen, Karam, Kim, Min Soo, Mitsche, Matthew, Garland, Kristina, Anderson, Norma, Noureddine, Lama, Pontoglio, Marco, Patel, Vishal, Xie, Yang, DeBose-Boyd, Russell, Igarashi, Peter Show More Hide
Publisher(s):
American Society of Nephrology (ASN)
Tags:
Medicine
article description
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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