Abstract
BackgroundHepatocyte nuclear factor 4α (HNF4α), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response. In order to obtain a genomic view of HNF4α in this context, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokine stimulation in a model of HNF4α knock-down in HepG2 cells.ResultsThe expression of over five thousand genes in HepG2 cells is significantly changed with the dramatic reduction of HNF4α concentration compared to the cells with native levels of HNF4α. Over two thirds (71%) of genes that exhibit differential expression in response to cytokine treatment also reveal differential expression in response to HNF4α knock-down. In addition, we found that a number of HNF4α target genes may be indirectly mediated by an ETS-domain transcription factor ELK1, a nuclear target of mitogen-activated protein kinase (MAPK).ConclusionThe results indicate that HNF4α has an extensive impact on the regulation of a large number of the liver-specific genes. HNF4α may play a role in regulating the cytokine-induced inflammatory response. This study presents a novel function for HNF4α, acting not only as a global player in many cellular processes, but also as one of the components of inflammatory response in the liver.
Highlights
Hepatocyte nuclear factor 4a (HNF4a), a liver-specific transcription factor, plays a significant role in liver-specific functions
Knock-down endogenous HNF4a in HepG2 cells To study the role of HNF4a in liver-specific gene expression and the inflammatory response, the endogenous HNF4a in HepG2 cells was knocked down by the technique of RNA interference
Our results indicate that HNF4a short hairpin RNA (shRNA) can efficiently and knock-down HNF4a in HepG2 cells [21]
Summary
Hepatocyte nuclear factor 4a (HNF4a), a liver-specific transcription factor, plays a significant role in liver-specific functions. Hepatocyte nuclear factor 4a (HNF4a) is a highly conserved member of the nuclear receptor superfamily It is highly expressed in liver, kidney, intestine, and pancreas in mammals. In contrast to the liver-enriched transcription factors HNF1a, HNF3a, HNF6, and CAAT/enhancer-binding protein (C/EBP)a, which when disrupted in the mouse genome the mice are viable but show specific effects on hepatocyte differentiation, metabolic function, and gene expression [3,4,5,6], disruption of the mouse HNF4a gene is embryonic. Trauma or infection results in the release of proinflammatory cytokines, e.g., interleukin (IL)-6, IL-1, and tumor necrosis factor-a (TNF-a) The release of these cytokines has long been known to stimulate the acute phase response (APR) and rapidly alters rates of synthesis of a group of plasma proteins known as acute phase proteins (APPs) [14]. An understanding of the molecular events that are involved in mediating the response to external stresses can lead to the development of therapeutic strategies for preventing the progression of the APR to the chronic inflammatory states, while preserving its protective effects
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