Fig. 1.

Mechanism of action of metformin in nonalcoholic fatty liver disease. (A) Decrease in de novo lipogenesis: (1) AMPK activation and increase inhibitory phosphorylation of ACC; (2) inhibition of ROCK-1 by metformin resulting in inhibitory phosphorylation of ACC; and (3) increase in leptin sensitivity attenuates de novo lipogenesis pathway. Decreasing fatty acyl CoA also decreases hepatic steatosis, decreases lipid-induced ER stress and decreases substrate for FA β-oxidation. (B) Increase in FA β-oxidation: (3) increase in leptin sensitivity induces PPARα-dependent FA β-oxidation; (4) up-regulation of proteins involved in mitochondrial lipid oxidation by metformin results in increased FA breakdown and energy combustion. (C) Decrease in inflammation and HSC activation: (5) decreased lipid-induced ER stress and oxidative stress due to decreased de novo lipogenesis; (6) TNF-α reduction decreases Kupffer cell and HSC activation resulting in reducing inflammation and fibrosis in the liver. (D) Direct degradation of intracellular lipid: (7, 8) induction of autophagy by restoration of SIRT1 activity causing lipolysis by lysosome (lipophagy).

ACC, acetyl-CoA carboxylase; CPT-1, carnitine palmitoyltransferase; ECM, extracellular matrix proteins; ER, endoplasmic reticulum; FA, fatty acid; FAS, fatty acid synthase; HSC, hepatic stellate cells; LepR, leptin receptor; Monounsat. LC-FAs, monounsaturated long-chain FAs; P-AMPK, phosphorylated AMP-activated protein kinase; PPARα, peroxisome proliferator-activated receptor gamma coactivator-1α; ROCK1, Rho-kinase 1; Sat., saturated; SCD, stearoyl-CoA desaturase; SIRT1, sirtuin 1; SREBP-1c, sterol regulatory element-binding protein 1; TNF-α, tumor necrosis factor.