Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels

Abstract

Nonalcoholic fatty liver disease (NAFLD) patients with diabetes constitute a subgroup of patients with a high rate of liver-related complications. Currently, there are no specific drug recommendations for these patients. Metformin, a conventional insulin sensitizer agent, has been widely prescribed in patients with diabetes. Metformin treatment has been shown to be effective at alleviating hepatic lipogenesis in animal models of NAFLD, with a variety of mechanisms being deemed responsible. To date, most studies have enrolled diabetic patients who are treated with metformin, with the drug being taken continuously throughout the study. Although evidence exists regarding the benefits of metformin for NAFLD in preclinical studies, reports on the efficacy of metformin in adult NAFLD patients have had some discrepancies regarding changes in liver biochemistry and hepatic fat content. Evidence has also suggested possible effects of metformin as regards the prevention of hepatocellular carcinoma tumorigenesis. This review was performed to comprehensively summarize the available in vitro, in vivo and clinical studies regarding the effects of metformin on liver steatosis for the treatment of adult NAFLD patients with diabetes. Consistent reports as well as controversial findings are included in this review, and the mechanistic insights are also provided. In addition, this review focuses on the efficacy of metformin as a monotherapy and as a combined therapy with other antidiabetic medications.

Keywords: Diabetes mellitus; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis.

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.

Fig. 2

Future directions. NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma.