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

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