LAUSR.org creates dashboard-style pages of related content for over 1.5 million academic articles. Sign Up to like articles & get recommendations!

MLN4924 Treatment Diminishes Excessive Lipid Storage in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Stimulating Hepatic Mitochondrial Fatty Acid Oxidation and Lipid Metabolites

Photo from wikipedia

MLN4924 is a selective neddylation inhibitor that has shown great potential in treating several cancer and metabolic diseases, including obesity. However, it remains largely unknown whether MLN4924 has similar effect… Click to show full abstract

MLN4924 is a selective neddylation inhibitor that has shown great potential in treating several cancer and metabolic diseases, including obesity. However, it remains largely unknown whether MLN4924 has similar effect on non-alcoholic liver disease (NAFLD), which is closely associated with metabolic disorders. Here, we investigated the role of MLN4924 in NAFLD treatment and the underlying mechanism of the action using primary hepatocytes stimulated with free fatty acid, as well as high-fat diet (HFD)-induced NAFLD mouse models. We found that MLN4924 can inhibit the accumulation of lipid and reduce the expression of peroxisome proliferator-activated receptor γ (PPARγ), a key player in adipocyte differentiation and function in both in vivo and in vitro models. Moreover, we verified its important role in decreasing the synthesis and accumulation of fat in the liver, thus mitigating the development of NAFLD in the mouse model. The body weight and fat mass in MLN4924-treated animals were significantly reduced compared to the control group, while the metabolic activity, including O2 consumption, CO2 and heat production, also increased in these animals. Importantly, we demonstrated for the first time that MLN4924 can markedly boost mitochondrial fat acid oxidation (FAO) to alter liver lipid metabolism. Finally, we compared the metabolites between MLN4924-treated and untreated Huh7 cells after fatty acid induction using lipidomics methods and techniques. We found induction of several metabolites in the treated cells, including Beta-guanidinopropionic acid (b-GPA) and Fluphenazine, which was in accordance with the increase of FAO and metabolism. Together, our study provided a link between neddylation modification and energy metabolism, as well as evidence for targeting neddylation as an emerging therapeutic approach to tackle NAFLD.

Keywords: disease nafld; non alcoholic; fatty; liver disease; fatty acid

Journal Title: Pharmaceutics
Year Published: 2022

Link to full text (if available)


Share on Social Media:                               Sign Up to like & get
recommendations!

Related content

More Information              News              Social Media              Video              Recommended



                Click one of the above tabs to view related content.