Hepatocyte nuclear factor 4α contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation

Abstract

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a regulator of hepatocyte and pancreatic transcription. Hnf4alpha deletion in the mouse is embryonically lethal with severe defects in visceral endoderm formation. It has been concluded in the past that the role of Hnf4alpha in the developing colon was much less important than in the liver. However, the precise role of Hnf4alpha in the homeostasis of the small intestinal epithelium remains unclear. Our aim was to evaluate the potential of Hnf4alpha to support an intestinal epithelial phenotype. First, Hnf4alpha potential to dictate this phenotype was assessed in nonintestinal cell lines in vitro. Forced expression of Hnf4alpha in fibroblasts showed an induction of features normally restricted to epithelial cells. Combinatory expression of Hnf4alpha with specific transcriptional regulators of the intestine resulted in the induction of intestinal epithelial genes in this context. Second, the importance of Hnf4alpha in maintaining the homeostasis of the intestinal epithelium was investigated in mice. Mice conditionally deficient for intestinal Hnf4alpha developed normally throughout adulthood with an epithelium displaying normal morphological and functional structures with minor alterations. Subtle but statistical differences were observed at the proliferation and the cytodifferentiation levels. Hnf4alpha mutant mice displayed an increase in the number of goblet and enteroendocrine cells compared with controls. Given the fundamental role of this transcription factor in other tissues, these findings dispute the crucial role for this regulator in the maintenance of intestinal epithelial cell function at a period of time that follows cytodifferentiation but may suggest a functional role in instructing cells to become specific to the intestinal epithelium.

Modification in Oxidative Stress, Inflammation, and Lipoprotein Assembly in Response to Hepatocyte Nuclear Factor 4α Knockdown in Intestinal Epithelial Cells

“…Surprisingly, limited work has been devoted to the gut even though HNF4␣ is at the crossroads between intestinal morphogenesis and function. As reported previously, HNF4␣ plays a role in colon development (17), intestinal epithelial cell differentiation, and phenotype expression (18,19). Interestingly, not only did HNF4␣ regulate the expression of many genes such as apolipoproteins (apo) (20 -25), but it also has been found associated with susceptibility to abnormal intestinal permeability and inflammation (26).…”

Transcription Factors GATA4 and HNF4A Control Distinct Aspects of Intestinal Homeostasis in Conjunction with Transcription Factor CDX2

“…Because defects in cell membranes and in nutrient absorption should be objectively observable, we focused efforts on identifying these deficits in Hnf4a del Cdx2 del mice. Apical microvilli in Hnf4a del mice are grossly intact (19). In contrast, microvilli on the apical membranes of Cdx2 del enterocytes were moderately scant and stunted, whereas those in Hnf4a del Cdx2 del cells were sparse, shortened, and disarrayed (Fig.…”

“…GATA4 and GATA6 show regional (proximal 4/5) and global intestinal expression, respectively, and the corresponding mutant mice have subtle defects in crypt cell replication, secretory cell differentiation, and control of selected enterocyte genes (15)(16)(17). Loss of HNF4A perturbs colon development (18), but Hnf4a Ϫ/Ϫ adult mouse intestines are overtly normal, with modestly perturbed gene expression (19). Coupled with the frequent co-occurrence of their specific sequence motifs near CDX2-binding sites, the limited defects in Gata and Hnf4a mutant mice led us to postulate that they may regulate intestinal genes in combination with CDX2.…”

“…The absence of HNF4A alone has little consequence on intestinal function (19) or chromatin structure, but the combined absence of CDX2 and HNF4A affects more transcripts than loss of either TF alone (24). To determine the functional consequences of combined TF loss, we produced Hnf4a del Cdx2 del intestines, which showed total or nearly total loss of CDX2 and HNF4A mRNA and protein throughout (Fig.…”

Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice

“…HNF-4 ␣ global deletion in the mouse is lethal, resulting in defective visceral endoderm and its differentiation into functional colon (12)(13)(14)(16)(17)(18). We previously reported the transcriptional activity of HNF-4 ␣ to be modulated by the CoAthioesters of long-chain fatty acids (LCFA) as a function of their chain length and degree of saturation ( 19 ).…”