Fatty Acid Synthase Inhibitor Platensimycin Intervenes the Development of Nonalcoholic Fatty Liver Disease in a Mouse Model.

Meng Su,Zhe Wang,Yong Huang,Danfeng Cao,Yanwen Duan

doi:10.3390/biomedicines10010005

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI4-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated the Western diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor α and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, which may further progress to non-alcoholic steatohepatitis (NASH) with hepatocyte damage and inflammation [1]
We provide the first evidence that PTM and PTM-loaded liposomes could prevent the development of NAFLD in a murine model induced by WD/CCl4
Using a free fatty acids (FFAs)-induced HepG2 cell model, we showed that PTM could attenuate lipid accumulation through the down-regulation of fatty acid synthase (FASN) and several key proteins for lipogenesis, including SREBP-1c, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase 1 (SCD1)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, which may further progress to non-alcoholic steatohepatitis (NASH) with hepatocyte damage and inflammation [1]. The NAFLD epidemic affects about 25% of the global population, with a significant increase in Asia [2,3]. 40% of these patients are classified as non-obese and almost a fifth of them are lean, while they might develop liver cirrhosis more rapidly than obese individuals with NAFLD [4,5]. NAFLD is identified as an important risk factor for severe coronavirus disease 2019 (COVID-19) outcomes, probably due to the increased expression of angiotensin converting enzyme 2 and transmembrane protease serine 2 in multiple tissues of NAFLD patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [7,8]. One major reason is that NAFLD is a multisystemic disease with successive liver abnormalities and extra-hepatic complications.

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Conclusion