Nonalcoholic fatty liver disease (NAFLD) is quickly becoming the most common liver disease around the world due to the increase of overeating and sedentary lifestyle (Younossi et al., 2018). This change in lifestyle increases the rate of obesity in adults and children alike. Obesity in childhood and adolescents increases the risk of developing NAFLD later in life (Younossi et al., 2018). Additionally, NAFLD increases the risk of developing metabolic diseases such as type 2 diabetes mellitus and other more serious diseases such as cirrhosis and cardiovascular disease (Samuel & Shulman, 2018; Younossi et al., 2018). Therefore, the need to manage and treat NAFLD is higher than ever. Unfortunately, there are no current treatments for NAFLD. However, studies activating AMP-activated protein kinase (AMPK) have shown some potential for treating metabolic diseases.
AMPK is protein kinase that inhibits the enzyme, Acetyl-CoA carboxylase, preventing new lipid synthesis in the body and increasing fatty acid oxidation for energy usage (Fullerton et al., 2013). Additionally, activation of AMPK downregulates some of the genes responsible for lipid synthesis in the body (Smith & Steinberg, 2017). This decreases the amount of lipids circulating the body potentially reducing the risk of developing metabolic diseases associated abnormal lipid metabolism. Furthermore, AMPK activation may improve mitochondrial integrity in adipose tissue as well as protect the organs and skeletal muscle from the redirection of fatty acids and lipids (Smith & Steinberg, 2017). The potential drawbacks of direct AMPK include: adverse epigenetic changes to the liver, impairments to glucose homeostasis, and a potential increase in reactive oxygen species due to the increase in beta oxidation metabolism (Smith & Steinberg, 2017).
Using genetically engineered mouse models (GEMMs), it was recently discovered that hepatic AMPK is protective against diet-induced obesity and NAFLD (Garcia et al., 2019). Researchers were able to develop a GEMM where liver specific AMPK could be activated in vivo. AMPK activation reduced inflammation of the liver and steatosis (accumulation of fat in the liver) through an incrase in fatty acid oxidation, the inactivation of new lipid synthesis, and autophagy activation in the obese mice (Garcia et al., 2019). Thus the activation of hepatic AMPK may delay the development of NAFLD and other metabolic disease. Hepatic AMPK activation also prevents the enlargement of white adipose tissue in mice with a high-fat diet (Garcia et al., 2019). Therefore, hepatic AMPK activation prevented the mice with a high-fat diet from becoming obese. Furthermore, the development of the inducible AMPK activation GEMM platform can be used to test potential therapeutics developed for AMPK activation. Although the research with AMPK activation is fairly new, the results of this study and others like it are promising. Further research with AMPK activation may lead to the development of therapeutics not only for NAFLD, but for other metabolic disease as well.
References
Garcia, D., Hellberg, K., Chaix, A., Wallace, M., Herzig, S., Badur, M. G., ... & Saghatelian, A. (2019). Genetic liver-specific AMPK activation protects against diet-induced obesity and NAFLD. Cell reports, 26(1), 192-208. doi: 10.1016/j.celrep.2018.12.036 Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z. P., ... & Hardie, D. G. (2013). Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature medicine, 19(12), 1649. doi: 10.1038/nm.3372 Samuel, V. T., & Shulman, G. I. (2018). Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell metabolism, 27(1), 22-41. doi: 10.1016/j.cmet.2017.08.002 Smith, B. K., & Steinberg, G. R. (2017). AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity. Current Opinion in Clinical Nutrition & Metabolic Care, 20(4), 248-253. doi: 10.1097/MCO.0000000000000380 Younossi, Z., Anstee, Q. M., Marietti, M., Hardy, T., Henry, L., Eslam, M., ... & Bugianesi, E. (2018). Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nature reviews Gastroenterology & hepatology, 15(1), 11. doi: 10.1038/nrgastro.2017.109
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