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

Table 1 Expression of hepatocyte nuclear factor 4alpha and variants in various disease states

Disease state	HNF4α expression	Organism	Model	Ref.
Development
Hypertriglyceridemia (preterm infants, children)	Decreased, P1 promoter methylation	Human	-	[8,9]
Intrauterine growth restriction	Decreased, hypermethylated promoter	Human	-	[73]
High fat diet (in utero)	Increased	Mouse	HFD	[87]
Metformin exposure (in utero)	Increased, hypomethylated promoter	Mouse	Metformin	[74]
Liver
Acute phase response	Decreased activity	Mouse	Injury	[15]
Inflammation (IL-1β)	Decreased	Human, mouse	Hepatoma cells	[14]
TNFα-induced hepatotoxicity	Decreased	Human, Mouse	Hepatoma cells	[88,89]
Alcoholic liver disease	Decreased	Mouse	Ethanol, MCD diets	[17,89]
α1-antitrypsin	Decreased	Mouse	Human ATZ	[90]
Fibrosis	Decreased	Human	Hepatocytes	[24]
Cirrhosis	Decreased	Human, rat	DEN	[41,91]
Hepatocellular carcinoma	P2 increased, P1 decreased	Human, rat	DEN	[32,41,59]
	Decreased, expressed in metastases, increased P1:P2	Human, mouse, rat	HCC cells, DEN	[13,31,33,40,41,59,92]
Hepatitis B virus	Decreased	Human	Hepatoma cells	[46,47]
Hepatitis C virus	Increased	Human	Hepatoma cells	[93,94]
	Decreased	Human, mouse	Hepatocytes, hepatoma cells, HCV+ HCC	[35,95]
Hepatitis E virus	Increased phosphorylation, cytoplasmic retention	Human	Hepatoma cells	[48]
Non-alcoholic steatohepatitis	Modestly increased	Human	-	[21]
	Decreased, cytoplasmic retention	Mouse	db/db or HFD	[18,22]
Iron overload	Decreased	Human, mouse	Hepatoma cells, iron rich diet	[49]
Endocrine
Type 2 diabetes	Decreased, P1 promoter hypermethylation	Human	-	[72]
	Increased in liver	mouse	HFD, steptozotocin	[76]
Mature onset diabetes of the young (MODY)	HNF4α variants	Human	-	[66-69]
Obesity	HNF4α variant	Human	-	[79]
Islet cell hypoxia	Decreased	mouse	ob/ob	[96]
Intestine
Micrbiome colonization	Decreased	Zebrafish	-	[52]
IBD	Decreased	Human, mouse	-	[56,57]
Crohn disease	HNF4α variant, decreased	Human	-	[55,56,98]
Ulcerative colitis	HNF4α variant	Human	-	[53,54]
Colorectal carcinoma	Decreased or cytoplasmic retention, altered P1:P2, expressed in metastases	Human, mouse	Mutagen	[59,99,100]
Intestinal type ampullary carcinoma	Increased	Human	-	[10]
Upper GI
Gastric carcinoma	Increased, altered P1:P2	Human	Carcinoma cells	[59,62,78,102]
Barrett esophagus (intestinal metaplasia)	Increased	Human, mouse	Explant	[63,64]
Stomach intestinal metaplasia	Increased	Human	-	[59]
Kidney
Renal cell carcinoma	Decreased, expressed in metastases, increased P1:P2	Human	-	[59,103,104]
Atypical fanconi syndrome	HNF4α variant	Human	-	[66]
Lung
Mucinous adenocarcinomas	Increased in some	Human	-	[82,100]
Ovary
Ovarian mucionous neoplasm	Expressed	Human	-	[81]
Heart
Cardiac fibrosis	Increased	Mouse	Angiotensin II	[83]

IL-1β: Interleukin 1beta; MCD: Methionine-choline deficient; HFD: High fat diet; TNFα: Tumor necrosis factor alpha; ATZ: Mutant Z form of alpha1-antitrypsin deficiency (ATD); HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; IBD: Inflammatory bowel disease.

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.