Metformin Applications in Hepatic Metabolism Disorders

Metformin, a first-line antidiabetic agent, has emerged as a versatile modulator of hepatic metabolism beyond its glycaemic control properties. In the liver, metformin primarily activates the adenosine monophosphate-activated protein kinase (AMPK) pathway, leading to suppression of gluconeogenesis, lipogenesis and cholesterol synthesis. This action translates into reduced hepatic steatosis and improved lipid profiles in non-alcoholic fatty liver disease (NAFLD). Further mechanistic layers include modulation of endoplasmic reticulum stress, attenuation of inflammatory signalling in hepatocytes and non-parenchymal cells, and alteration of the gut–liver axis via changes in microbiota composition. Preclinical models also indicate that metformin can impede activation of hepatic stellate cells, thereby slowing fibrogenesis, and may enhance the efficacy of antitumour agents in hepatocellular carcinoma. Clinically, metformin has shown modest but consistent reductions in serum transaminases, triglycerides and insulin resistance. Its low cost, favourable safety profile and global availability underscore its public-health relevance as an adjunctive therapy in a spectrum of hepatic metabolism disorders.

Research from Nature Portfolio

Recent mechanistic work has uncovered a transcriptional axis by which metformin directly inhibits key anabolic programmes in hepatocytes. By downregulating the steroid receptor coactivator 2 (SRC-2), metformin reduces recruitment of transcriptional machinery to promoters of gluconeogenic and lipogenic enzymes. This leads to diminished expression of glucose-6-phosphatase, fatty acid synthase and other sterol regulatory element-binding protein targets, resulting in measurable decreases in both glucose output and intracellular lipid accumulation. The study highlights SRC-2 as a nodal regulator mediating metformin’s dual suppression of gluconeogenesis and lipogenesis, thus providing a unifying insight into its multifaceted hepatic actions.

Metformin Applications in Hepatic Metabolism Disorders publication trend

The graph below shows the total number of articles in metformin applications in hepatic metabolism disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Adenosine monophosphate-activated protein kinase (AMPK): An intracellular energy sensor that, when activated, inhibits anabolic and promotes catabolic pathways.

Non-alcoholic fatty liver disease (NAFLD): A spectrum of liver conditions characterised by excessive fat accumulation in hepatocytes in the absence of significant alcohol intake.

Steroid receptor coactivator 2 (SRC-2): A transcriptional coactivator that enhances expression of gluconeogenic and lipogenic genes in the liver.

Pyroptosis: A proinflammatory form of programmed cell death marked by cell swelling, membrane rupture and release of inflammatory mediators.

Gluconeogenesis: The metabolic synthesis of glucose from non-carbohydrate substrates, principally in the liver.

Lipogenesis: The process of synthesising fatty acids and triglycerides within hepatocytes.

References

1. Metformin induces pyroptosis in leptin receptor-defective hepatocytes via overactivation of the AMPK axis. Cell Death & Disease (2023).
2. Metformin: update on mechanisms of action on liver diseases. Frontiers in Nutrition (2023).
3. Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2). Scientific Reports (2015).
4. Effect of metformin on nonalcoholic fatty liver based on meta-analysis and network pharmacology. Medicine (2022).