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

ABSTRACT: HNF-1? is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1? develop kidney cysts, and HNF-1? regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1?-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-1? in murine kidney epithelial cells. Pathway analysis predicted that HNF-1? regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1? or kidney-specific inactivation of HNF-1? 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-1? 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-1? on the proteins encoded by Srebf2 and Hmgcr, and HNF-1? 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-1? in a transcriptional network that regulates intrarenal cholesterol metabolism.

SUBMITTER: Aboudehen K 

PROVIDER: S-EPMC4978044 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature