Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.
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.
['Aboudehen|Karam|K|', 'Kim|Min Soo|MS|', 'Mitsche|Matthew|M|', 'Garland|Kristina|K|', 'Anderson|Norma|N|', 'Noureddine|Lama|L|', 'Pontoglio|Marco|M|', 'Patel|Vishal|V|', 'Xie|Yang|Y|', 'DeBose-Boyd|Russell|R|', 'Igarashi|Peter|P|']
D000818:Animals D002784:Cholesterol D051539:Hepatocyte Nuclear Factor 1-beta D007668:Kidney D051379:Mice
transcription factors lipids polycystic kidney disease