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.