TABLE 1.

The role of nuclear receptors in hepatic cholesterol metabolism and NAFLD

Gene name	Nuclear receptor	Ligand	Function in cholesterol metabolism and NAFLD	References
NR0B1	DAX1	Orphan	DAX-1 inhibits the transcriptional activity of LRH-1 and LXRα, and inhibits gluconeogenesis by negatively regulating HNF4A	55–57
NR0B2	SHP	Orphan	The expression of SHP inhibits CYP7A1, and downregulation of SHP accelerates the transformation of cholesterol to bile acids by activating CPY7A1	58,59
NR1A1	TRα	Thyroid hormones	Downregulation of TRα alleviates diet-induced hepatic steatosis	60,61
NR1A2	TRβ	Thyroid hormones	Loss of TRβ shows excessive lipid accumulation in both human and mouse livers	62–64
NR1B1	RARα	Retinoic acids	Loss of RARα-induced hepatic steatosis and decreased macrophage cholesterol effection in HFD-fed mice. Upregulation of RARα could reduce hepatic lipid accumulation by decreasing CD36 expression	65–67
NR1B2	RARβ	Retinoic acids	Upregulation of RARβ can alleviate hepatic lipid accumulation in hepatocytes	68,69
NR1B3	RARγ	Retinoic acids	Upregulation of RARγ activates ABCA1-mediated cholesterol efflux	70
NR1C1	PPARα	Fatty acids	Metabolomics has revealed that PPARα is an important regulator of bile acids by interacting with SREBP2, and that PPAR-α/γ agonist Saroglitazar significantly improves insulin resistance and dyslipidemia in NAFLD	71–73
NR1C2	PPARβ	Fatty acids	PPARβ/δ inhibits CYP7a1 expression by upregulating FGF21	74
NR1C3	PPARγ	Fatty acids	PARγ inhibitor GW9662 can reduce the development of NAFLD by inhibiting TLR4, but PPARγ can promote cholesterol effluence by inducing the expression of ABCA1 in gallbladder epithelium	75,76
NR1D1	REV-ERBα	Heme	REV-ERB coordinates the regulation of most genes encoding important enzymes in the cholesterol biosynthesis pathway, and downregulation of Rev-ERbα promotes bile acid metabolism through upregulation of CYP7A1	77–79
NR1D2	REV-ERBβ	Heme	Activation of REV-ERBα/β reduces hepatic triglyceride storage and inhibits cholesterol synthesis, and can increase promoter activity of CYP7A1	80,81
NR1F1	RORα	Sterols	Overexpression of RORα reduces diet-induced hepatic lipid accumulation, and its inverse agonist SR1001 regulates intestinal excretion of cholesterol by upregulating ABCG5/G8	82,83
NR1F3	RORγ	Sterols	Knockout of RORγ may reduce bile acid synthesis by decreasing levels of Cyp8b1, Cyp7b1, and Cyp27a1	84
NR1H4	FXRα	Bile acids	FXRα can promote CYP7A1 expression through FGF19 and SHP/LRH-1 pathway, competitively inhibit LXRα to promote CETP transcription and reduce liver cholesterol uptake and accumulation	85–87
NR1H3	LXRα	Oxysterols	LXRα activates ABCG5/8 to promote the excretion of cholesterol in bile. LXRα can promote cholesterol effection in gallbladder epithelium by inducing the expression of ABCA1. LXRα deficiency leads to downregulation of CYP7A1 level, leading to liver cholesterol accumulation	76,88,89
NR1H2	LXRβ	Oxysterols	LXRβ agonists induce the expression of cholesterol pump ABCA1 in bile duct cells and promote the output of cholesterol from the basolateral membrane of bile duct cells	90
NR1I1	VDR	1α,25‐dihydroxyvitamin D3	VDR is significantly highly expressed in NAFLD, and its deficiency leads to reduced fat accumulation when aging and adult mice are fed a high-fat diet	91,92
NR1I2	PXR	Endobiotics and xenobiotics	PXR aggravated hepatic steatosis caused by a high-fat diet, and PXR KO mice had significantly reduced levels of liver triglycerides, hepatic steatosis, serum total bile acids, and liver gene expression of enzymes involved in the bile acid synthesis pathway	93,94
NR1I3	CAR	Xenobiotics	CAR is able to confer hepatoprotection from bile acids by increasing their sulfation and excretion	95,96
NR2A1	HNF4α	Fatty acids	Loss of HNF4α enhances hepatic cholesterol accumulation by inhibiting CYP7A1/CYP8B1, FXR, and ABCAS1, and loss of HNF4α in mice shows hepatic steatosis and reduced plasma cholesterol levels	97–99
NR2B1	RXRα	9‐Cis retinoic acid	RXRα serves as a heterodimerization partner for PPARα, PXR, LXR, and FXR to participate in the regulation of cholesterol metabolism	100–104
NR2C2	TR4	Orphan	TR4 knockout reduces liver lipid accumulation and can reduce apoE levels	105,106
NR2E1	TLX	Orphan	Mice with NR2E1 knocked out display a significant hepatic steatosis phenotype	107
NR2F1	COUP-TFα	Orphan	COUP-TFα exerts a transcriptional repression effect by binding to the promoter region of apoCIII	108
NR2F2	COUP-TFβ	Orphan	HNF4 and coup-TF-β synergistically activate the transcription of the CYP7A1 promoter	109,110
NR2F6	EAR2	Orphan	EAR2 inhibits the transcription of the genes encoding apoB, apoCIII, and apoAII	111
NR3A1	ERα	Estrogens	ERα upregulates the expression of intestinal Npc1l1, Abcg5 and Abcg8, inhibits the transcriptional activity of LXRα in liver, and interacts with FXR in an estradiol-dependent manner to inhibit its function in vitro	112–114
NR3A2	ERβ	Estrogens	Absence of Erβ alleviates the disruption of bile acid and cholesterol metabolism induced by perfluorooctane sulfonate	115
NR3B1	ERRα	Orphan	VLDL-TG secretion is reduced in ERRα KO mice, leading to hepatic steatosis	116
NR3B3	ERRγ	Orphan	Overexpression of ERRγ upregulates the expression of CYP7A1 both in vitro and in vivo	117
NR3C1	GR	Glucocorticoids	GR interacts with FXR to reduce FXR transcriptional activity and promote hepatic cholestasis in mice by recruiting CtBP coblocking complex, and GR regulator CORT118335 can reverse hepatic cholesterol accumulation	118,119
NR3C2	MR	Mineralocorticoids and glucocorticoids	Specific blockade of MR exhibits hepatic antisteatotic effects	120
NR3C4	AR	Androgens	AR reduces cholesterol synthesis by mediating phosphorylation of HMGCR and promotes cholesterol synthesis and accumulation by activating sterol-regulatory element-binding protein isoform 2	121,122
NR4A1	Nur77	Orphan	Nur77 regulates liver lipid metabolism by inhibiting SREBP1c activity, and the levels of TCHO, LDLR, HMGCR, and Nur77 in HepG2 cells are negatively correlated	123,124
NR5A2	LRH‐1	Phospholipids	LRH-1 regulates hepatic cholesterol excretion through CYP7A1 and CYP8B1	125

Abbreviations: ABCA1, ATP-binding cassette transporter A1; CYP7A1, cytochrome P450; FXR, farnesoid X receptor; HNF4α, hepatocyte nuclear factor 4 alpha; KO, knockout; LDLR, LDL receptor; LXR, liver X receptor; PPAR, peroxisome proliferator-activated receptor; SHP, small heterodimer partner.