Investigating the involvement of small intestine in metformin's effect on hepatic lipid metabolism

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Project Summary Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), there are currently no approved medications to treat NAFLD. Metformin is frequently discussed as a promising treatment for NAFLD but reports on the efficacy of metformin in NAFLD patients are not consistent. Hence, the effect of metformin on hepatic lipid metabolism and the underlying mechanisms warrant further research. Metformin is thought to directly regulate hepatic lipid metabolism via activating hepatic AMP-activated protein kinase (AMPK), which subsequently inhibits de novo lipogenesis and promotes fatty acid oxidation in liver. However, there is a lack of quantitative assessment of to what extent hepatic lipogenesis or fatty acid oxidation is affected by metformin in vivo. In addition, due to high concentrations of metformin in the intestine, the intestine has emerged as an important action site of metformin. Dr. Huang generated intestinal epithelium-specific AMPK alpha 1 knockout mice and observed that the beneficial effect of metformin was attenuated in these mice (Nature Communications 2022), suggesting that the action of metformin in intestine is required for correcting dietary-induced metabolic disorders. Due to the pleiotropic effects of metformin, omics analysis such as metabolomics, lipidomics, and 13C isotope tracing will be required to quantitively and systemically assess the metabolic effects of metformin in different organs. In a pilot study, I performed metabolomics and lipidomics analysis using liquid chromatography coupled to high resolution mass spectrometer (LC-HRMS). The preliminary data suggest that the number of metabolites and lipids altered by metformin positively correlated with concentrations of metformin in these tissues, and metformin-induced metabolic and lipidomic changes were more profound in intestine due to the high concentration in intestine. We also synthesized a metformin probe containing an alkyne group, which will be used to identify the molecular target of metformin. In the next five years, I will combine my expertise in omics analysis with metformin probe and genetically modified mice developed by Dr. Huang to test the hypothesis that metformin induces beneficial metabolic and lipidomic alterations in intestine, enhances intestinal functions (e.g., sugar clearance) and subsequently shields liver from dietary-induced damage. The immediate goal of this project is to elucidate the action site and underlying mechanisms through which metformin protects the liver against high fructose-induced metabolic damage. The long-term goal is to 1) develop strategies to enhance the metabolic capacity of intestinal epithelial cells for alleviating liver steatosis and 2) to provide insights into identifying NAFLD patients who likely benefit from metformin monotherapy and developing optimal strategies to prevent or treat NAFLD. Even though this proposed study is focused on metformin in the context of dietary- induced liver disease, methods and discoveries in this study are expected to make a broad impact in diseases with dysregulated metabolism.