Table 2.

Metformin Effects on Hepatic Inflammation, Oxidative Stress, and Fibrosis: Evidence from In Vivo Reports

Author (year)	Model (age)	Method	Metformin (dose/route/duration)	Effects of metformin	Interpretations
Studies showing effective intrahepatic lipid reduction by metformin
Stachowicz et al. (2012)38	Female C57BL/6J mice (8 weeks old)	- apoE-/-	- 10 mg/kg/day/PO/16 weeks	↑ PRDX-6	Metformin up-regulated antioxidant protein.
Guo et al. (2018)22	Male C57BL/6J mice (3 weeks old)	- HFD	- 3 mg/kg/day/PO/5 weeks - Starting after HFD for 12 weeks	↓ Hepatic TG, TC ↓ Hepatic CD68+ IHC staining	Metformin reduced macrophage content in the liver.
Khalaf et al. (2019)25	Male albino rats (200–250 g weight)	- 10% fructose in drinking water	- 300 mg/kg/day/PO/4 weeks	↓ Hepatic TG ↑ GSH, SOD ↓ MDA ↓ TNF-α ↓ Histologic steatosis ↔ Histologic inflammation ↓ iNOS stained cell	Metformin reduced oxidative stress and inflammatory mediators.
Li et al. (2019)20	Male C57BL/6J mice (6 weeks old)	- MCD diet	- 250 mg/kg/day/IP/4 weeks	↓ Histologic steatosis and inflammatory cell infiltration ↓ TNF-α, IL-1β, IL-6	Metformin reduced hepatic inflammatory markers.
de Jesús Acosta-Cota et al. (2019)28	Male Wistar rats (4 weeks old)	- 50% sucrose (wt/vol) in drinking water	- 200 mg/kg/day/PO/5 weeks - Starting after sucrose for 16 weeks	↔ Hepatic TG ↓ Hepatic TC ↔ TNF-α, IL-6, IL-10 ↓ TGF-β ↓ Number of rats with fibrosis	Metformin decreased hepatic cholesterol contents and TGF-β.
Brandt et al. (2019)26	Female C57BL/6J mice (6–8 weeks old)	- Fat/fructose-and cholesterol-rich diet	- 300 mg/kg/day/PO/4 days	↓ Hepatic TG ↓ Neutrophilic granulocytes ↔ TNF-α	Metformin treatment decreased inflammatory cell infiltration and TNF-α in the liver.
			- 300 mg/kg/day/PO/6 weeks	↔ Hepatic TG ↓ Neutrophilic granulocytes ↓ TNF-α
Studies showing ineffective intrahepatic lipid reduction by metformin
Matafome et al. (2011)31	Goto-Kakizaki rats (8 weeks old)	- HFD	- 60 mg/kg/day/PO/4 weeks - Starting after HFD for 12 weeks	↔ Hepatic TG, TC ↓ TNF-α ↔ IL-6, protein carbonyl, serum CRP	Metformin decreased TNF-α in liver.
Mahzari et al. (2019)29	Male C57BL/6J mice (10 weeks old)	- MCD diet	- 250 mg/kg/day/PO/6 weeks	↔ Hepatic TG ↔ TNF-α, CD68 mRNA ↔ Collagen 1, TGF-β, Smad3 ↔ Liver fibrosis area	Metformin did not improve NASH features and proteins associated with profibrotic pathways.

apoE^-/-, apolipoprotein E knock-out mutation; CRP, C-reactive protein; GSH, glutathione; HFD, high fat diet; IHC, immunohistochemical staining; IL, interleukin; IP, intraperitoneal route; iNOS, inducible nitric oxide synthase; MCD, methionine-and choline-deficient diet; MDA, malondialdehyde; NASH, nonalcoholic steatohepatitis; PRDX-6, peroxiredoxin 6; PO, per os; SOD, superoxide dismutase; TC, total cholesterol contents; TG, triglyceride content; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; ↓, significant decrease; ↑, significant increase; ↔, no significant change.