Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease

Table 1 Modulators of nuclear factor erythroid 2-related factor 2 pathway in metabolic associated fatty liver disease

Compound name	Species	Diet/duration	Treatment	Key findings	Reference
MonoHER	Female C57BL/6J mice (Ldlr-/-)	High fat and high cholesterol/13 wk	Administered daily subcutaneously at a dosage of 500 mg/kg of body weight (25 µL/g of body weight)	NRF2 activation, ↑GSH/GSSG ratio, ↑HO-1, GSH-Px	[62]
Scutellarin	Male C57BL/6 mice, hepaG2 cells	High fat/10 wk	Administration of 12.5, 25.0, and 50.0 mg/kg per day	↑PPARγ, PGC-1α, NRF2, HO-1, NQO1, Keap1, NF-κB	[33]
	Sprague-Dawley rats	High fat/12 wk	Administered orally 50, 100, and 300 mg/kg/d	NRF2, HO-1, NQO1; PI3K/AKT activation	[34]
Apigenin	Male C57BL/6J mice	High fat/16 wk	Injected intraperitonially 30 mg/kg daily for 3 wk	NRF2 activation; PPARγ inhibition; SOD, CAT, GSH-Px	[35]
7,8-dihydroxyflavone	Male wistar rats	High fat, ethanol/12 wk	Administered intraperitonially at 5 mg/kg/d for 4 wk	Amelioration of liver architecture, vescicular changes, infiltration; restored serum biomarkers like AST, ALT, and TC; ↑NRF2; ↓NF-κB	[63]
Resveratrol	Male C57BL/6 mice	High fat/16 wk	Supplemented with 0.4% resveratrol in HFD for 16 wk	Attenuated liver steatosis; ↑NRF2 activation; attenuated HFD induced methylation of NRF2 promoter; ↓oxidative stress	[68]
Quecertin	HepG2 cells	-	Treated with quecertin at 5-50 µM concentrations for 0, 10, 30, 60, 120, 240, and 1080 min	↑GSH, GSH-Px, GCS; p38-MAPK is involved in NRF2 modulation; ↓oxidative stress	[69]
Curcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)	Male C57BL/6 mice	High fat and high fructose/8 wk	Administered orally 50 and 100 mg/kg/d for 4 wk	↑CYP3A, CYP7A; regulation of NRF2/FXR/LXRα pathway; ↓SREBP-1C, FAS	[70]
	Male Sprague-Dawley rats	High fat/6 wk	Administered orally 50 mg/kg daily for 6 wk	↓Steatosis and inflammation; ↓Serum aminotransferases, lipids, and insulin resistance; ↓TNF, IL-6, MDA; ↑NRF2, GSH, HO-1, SOD	[71]
Oltipraz	Male Fischer 344 rats	Choline-deficient L-amino acid–defined/10 wk	Administered orally at 60 mg/kg/d for 9 wk	↑NRF2 activation; antifibrotic and anti-inflammatory; ↓AST and ALT; ↑NQO1 gene expression	[61]
GSTD	HL-7702 cells, male C57BL/6J, male Sprague-Dawley rats	Oleic acid (OA)/24 h, high fat/10 wk; high fat and high cholesterol/10 wk	Cells were treated with GSTD for 24 h, administered orally at 10, 20, 50 mg/kg per day for 10 wk, administered orally at 20, 50 mg/kg per day for 10 wk	↑NRF2, HO-1, SOD; activate AMPK/NRF2; ↓proinflammatory response, and hepatic steatosis; ↓MDA, ROS	[65]
NK-252 1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea)	Male Fischer 344 rats	Choline-deficient L-amino acid–defined/10 wk	Administered orally at 20, 60 mg/kg/d for 9 wk	Attenuated histological abnormalities; ↑antifibrotic effects; ↓TGF-β1, collagen α1; NRF2 activation; ↑NQO1 expression	[61]
Clusterin	Male hCLU-tg mice	MCD/3 wk	Generated hepatocyte-specific clusterin overexpression transgenic mice and fed with MCD diet	↓Hepatic TGs; less infiltration of macrophages; ↓TNF; ↑NRF2 activation and mRNA of HO-1	[66]
Osteocalcin	Male C57/BL6J mice	High fat/12 wk	Injected intraperitonially at concentration 3 ng/µL/d for 12 wk	↓Hepatic TG accumulation; ↑NRF2 activation; ↑CAT, SOD, GSH-Px; ↓JNK activation	[67]
Orlistat	Male Sprague-Dawley rats	High fat/12 wk	Administered at 10 mg/kg/d for 12 wk	↑NRF2 activation; protection against insulin resistance, hyperlipidemia, oxidative stress, and liver injury	[72]
Garcinia Cambogia	Male C57BL/6N mice	High fat/8 wk	Administered 200, 400 mg/kg/d for 8 wk	↑NRF2 activation; ↓ROS production; suppressed lipogenic factors C/EBPα and PPARγ; suppressed apoptosis by normalizing Bcl-2/BAX ratio and PARP cleavage	[73]
HTT	Male Sprague-Dawley rats, 3T3-L1 murine embryo fibroblast cells	High fat/4 wk, 3T3-L1 cells treated with FBS/DMEM for 8 d	Administered orally HTT at 350, 700, and 1400 mg/kg/d, 3T3-L1 cells treated with HTT at 500 µg/mL for 24 h or 48 h	↑NRF2-HO-1 activation, antioxidant activities; HTT inhibited liver weight gain; reduced lipid profile; improved liver function; HTT promoted lipolysis and increased antioxidant activities in 3T3-L1 cells	[74]
Hesperitin	HepG2 cells, male wistar rats	OA/24 h, high fat/16 wk	Treated cells at 0.25, 0.50, 1.00, 2.50, 5.00, and 10.00 µM; administered 100 mg/kg in 0.5% CMC-Na	Alleviated hepatotoxicity and oxidative stress by increasing SOD, GSH-Px, GCLC, and HO-1; ↑NRF2 activation; suppressed OA induced inflammation; reduced TC, TGs, and LDLC in a dose-dependent manner	[75]
Glucoraphanin	Male C57BL/6JSlc mice	High fat/14 wk	Administered 0.3% glucoraphanin orally for 14 wk	Decrease in weight gain; improved insulin resistance; reduced hepatic steatosis and oxidative stress; decrease in circulating LPS; ↑NRF2 activation; ↑energy expenditure and; UCP1 protein expression	[76]
Scutellaria baicalensis extract	Male KK-Ay mice	1% Orotic acid and 33% sugar/7 d	Supplemented with diet for 7 d	Diminished increase in liver weight; attenuated hepatic steatosis; ↑NRF2 expression; suppress SREBP-1c gene and protein expression	[77]
Ginkgolide B	Male C57/BL6 ApoE-/--mice, HepG2 cells	High fat/5 wk, 100 µM palmitic acid (PA) and 200 µM OA/24 h	Administered orally at 20, 30, and 1.3 mg/kg/d; treated cells at dosages 0, 1, 2, 4, 8, 16, and 32 µg/mL	NRF2 activation; inhibition of oxidative stress and lipid peroxidation through NRF2 pathway; increase in HO-1 and GSH-Px4	[78]
Scoparone	Male C57BL/6 J mice, AML2 and RAW264.7 cells	MCD/4 wk; AML12/300 µM PA and RAW264.7/10 µM/ Chloroquine	Administered daily intraperitonially for 4 wk at 20, 40, and 80 mg/kg; AML12 and RAW264.7 cells were pretreated with scoparone for 2 h	Ameliorated hepatic inflammation; improved hepatic autophagy; suppressed inflammation by inhibiting ROS/P38/NRF2 axis and PI3K/AKT/mTOR pathway	[79]
DA	Male C57BL/6J mice, HL7702 cells	High fat/12 wk, 0.6 mM OA/24 h	Administered by gavage at 10 and 20 mg/kg/d for 9 wk; treated with 2.5, 5.0, and 10.0 µM DA	Ameliorated liver ferroptosis in mice and cells; improved oxidative stress and lipid peroxidation in vivo; ↑NRF2-HO-1 expression; ↑GSH, GSH-Px4	[80]
Silibinin	Male C57BL/6 mice, NCTC-1469 cells	MCD/6 wk, OA plus PA/24 h	Administered by gavage at 10 and 20 mg/kg/d for 6 wk, 0.25 mM/L PA and 0.5 mM/L OA/24 h	Prevented CFLAR-JNK pathway; ↑β-oxidation and efflux of fatty acids; ↑expression of CAT, GSH, GSH-Px, and HO-1; ↓expression of CYP2E1 and CYP4A; ↑NRF2 activation	[81]
Chicoric acid	Male C57BL/6 mice	High fat/9 wk	Administered by gavage at 15 and 30 mg/kg/d for 9 wk	Attenuated hyperglycemia, dyslipidemia, and systemic inflammation; alleviated hepatic lipid accumulation and oxidative stress; suppressed hepatic inflammation and NF-κB pathway; ↑NRF2/Keap1 activation; improved gut microbiota	[82]
Carbon monoxide releasing molecule-A1	Male C57BL/6J mice	High fat/16 wk	Administered intraperitonially 2 mg/kg/d for 7 wk	↑NRF2/ARE activation; improved lipid homeostasis; ↑ATP production; improved mitochondrial biogenesis; ameliorated oxidative stress	[83]

NRF2: Nuclear factor erythroid 2-related factor 2; GSH: Reduced glutathione; GSSG: Oxidized glutathione; HO-1: Heme oxygenase-1; GSH-Px: Glutathione peroxidase; PPAR-γ: Peroxisome proliferator-activated receptor-γ; PGC-1α: Proliferator-activated receptor gamma coactivator-1α; NQO1: NAD(P)H quinone oxidoreductase 1; DA: Dehydroabietic acid; PA: Palmitic acid; NF-κB: Nuclear factor κ B; PI3K: Phosphatidylinositol 3’-kinase; SOD: Superoxide dismutase; CAT: Catalase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; TC: Total cholesterol; HFD: High-fat diet; GCS: Glutamylcysteine-synthetase; MAPK: Mitogen-activated protein kinase; CYP3A: Cytochrome P450, family 3, subfamily A, CYP7A Cytochrome P450, family 7, subfamily A; FXR: Farnesoid-X-receptor; LXRα: Liver X receptor α; SREBP-1C: Sterol regulatory element-binding protein-1c; FAS: Fatty acid synthase; TNF: Tumor necrosis factor; IL-6: Interleukin-6; MDA: Malondialdehyde; AMPK: AMP kinase; ROS: Reactive oxygen species; TGF-β1: Transforming growth factor-β1; TG: Triglycerides; JNK: c-Jun N-terminal kinase; C/EBPα: CCAAT/enhancer binding protein α; Bcl-2: B-Cell Leukemia/Lymphoma 2; BAX: BCL2 associated X protein; PARP: Poly-ADP ribose polymerase; HTT: Hedansanqi Tiaozhi Tang; GCLC: Glutamate cysteine ligase catalytic; LDLC: Low density lipoprotein cholesterol; LPS: Lipopolysaccharide; UCP1: Uncoupling protein 1; GSH-Px4: Glutathione peroxidase 4; mTOR: Mammalian target of rapamycin; CFLAR: CASP8 And FADD like apoptosis regulator; CYP2E1: Cytochrome P450 family 2 subfamily E member 1; CYP4A: Cytochrome P450 family 4 subfamily A; ARE: Antioxidant response element; AKT: Protein kinase B; MCD: Methionine- and choline-deficient; GSTD: Gastrodin; Keap1: Kelch-like ECH-associated protein 1.