Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases

Table 2 Effects of experimental perturbations of hepatocyte nuclear factor 4alpha

HNF4α manipulation	Organism	Model	Effect	Ref.
Development
Overexpression of α1D	Human	iPSCs	Promoted endoderm differentiation	[105]
Liver
Overexpression	Human	Marrow-derived mesenchymal stem cells	Epithelioid changes, glycogen storage, albumin secretion	[6]
	Rat	DEN	Suppressed carcinogenesis, suppressed EMT, decreased fibrosis, restored hepatic function in cirrhosis	[5,26,41]
	Rat	mst1/2 conditional mutant	Reduced liver size and HCC proliferative indices	[31]
	Mouse	Hepatoma cell xenograft	Decreased tumorigenesis and proliferation	[39,40]
	Mouse	Acute liver failure	Increased survival, urea production	[86]
Knockdown	Human	Hepatocyte culture, HBV infection	Increased hepcidin expression, impaired transcription and replication of HBV, transformation and tumorigenicity in mice	[13,36,42,43,106]
Liver targeted knockdown	Mouse	-	Increased hepatocyte proliferation and promitogenic transcription	[38]
Expression of α7 only	Mouse	-	Steatosis, downregulation of CAR	[75]
Liver targeted knockout	Mouse	DEN	Upregulation of miR-194 and -192, reduced transcriptional response to extracellular matrix rigidity, increased hepatocyte proliferation, HCC risk, steatosis	[20,24,107,108]
Intestine
Overexpression	Mouse, rat	Embryonal carcinoma cells, co-culture	Differentiation to polarized epithelium, tight junction proteins	[109,110]
Exon swapping, P1 or P2 only	Mouse	DSS	Altered enterocyte migration, ion transport, barrier function, susceptibility to DSS colitis and associated cancer	[2]
Intestine targeted knockout	Mouse	DSS	Transcription profiles similar to IBD, altered embyonic development, Paneth cell alterations, susceptibility to colitis	[50,56,111,112]
Intestine targeted knockout of P1 and P2	Mouse	-	Spontaneous intestinal inflammation	[57]
Dominant negative expression	Mouse, Human	Enterocytes	Decreased expression of apolipoprotein A	[113]
Upper GI
Esophagus overexpression	Mouse	Esophageal explants	Induced partial columnar cell phenotype	[63]
Stomach overexpression	Human	Gastric carcinoma cells	Resistance to multiple chemotherapeutics	[102]
Stomach knockdown	Human	Gastric carcinoma cells	Increased susceptibility to chemotherapeutics	[102]
Stomach targeted knockout	Mouse	-	Reduced chief cell size, epithelial proliferation and migration	[61]
Endocrine
HNF4α7 only expression	Mouse	-	Dyslipidemia, mild steatosis	[75]
HNF4α1 only expression	Mouse	-	Impaired glucose tolerance, hyperinsulinemia	[75]
Knockout in pancreatic beta cells	Mouse	-	Reduced glucose stimulated insulin secretin, similar to MODY	[65,70,71]
Overexpression in pancreatic beta cells	Human	islet cells	Induced cell cycle entry without expansion	[114]

iPSCs: Induced pluripotent stem cells; DEN: Diethylnitrosoamine; HBV: Hepatitis B virus; DSS: Dextran sodium sulfate; HNF47: Hepatocyte nuclear factor 4alpha7; HNF41: Hepatocyte nuclear factor 4alpha1.