Methylsulfonylmethane ameliorates metabolic-associated fatty liver disease by restoring autophagy flux via AMPK/mTOR/ULK1 signaling pathway

Daewon Han; Deokryong Kim; Haeil Kim; Jeonga Lee; Jungmook Lyu; Jong-Seok Kim; Jongdae Shin; Jeong Sig Kim; Do Kyung Kim; Hwan-Woo Park

doi:10.3389/fphar.2023.1302227

Methylsulfonylmethane ameliorates metabolic-associated fatty liver disease by restoring autophagy flux via AMPK/mTOR/ULK1 signaling pathway

Front Pharmacol. 2023 Nov 30:14:1302227. doi: 10.3389/fphar.2023.1302227. eCollection 2023.

Authors

Daewon Han^#^{1

2}, Deokryong Kim^#¹, Haeil Kim¹, Jeonga Lee¹, Jungmook Lyu³, Jong-Seok Kim², Jongdae Shin^{1

2}, Jeong Sig Kim⁴, Do Kyung Kim⁵, Hwan-Woo Park^{1

2}

Affiliations

¹ Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea.
² Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, Republic of Korea.
³ Department of Medical Science, Konyang University, Daejeon, Republic of Korea.
⁴ Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
⁵ Department of Anatomy, Konyang University College of Medicine, Daejeon, Republic of Korea.

^# Contributed equally.

Abstract

Introduction: Metabolism-associated fatty liver disease (MAFLD) is a global health concern because of its association with obesity, insulin resistance, and other metabolic abnormalities. Methylsulfonylmethane (MSM), an organic sulfur compound found in various plants and animals, exerts antioxidant and anti-inflammatory effects. Here, we aimed to assess the anti-obesity activity and autophagy-related mechanisms of Methylsulfonylmethane. Method: Human hepatoma (HepG2) cells treated with palmitic acid (PA) were used to examine the effects of MSM on autophagic clearance. To evaluate the anti-obesity effect of MSM, male C57/BL6 mice were fed a high-fat diet (HFD; 60% calories) and administered an oral dose of MSM (200 or 400 mg/kg/day). Moreover, we investigated the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin complex 1 (mTORC1)/UNC-51-like autophagy-activating kinase 1 (ULK1) signaling pathway to further determine the underlying action mechanism of MSM. Results: Methylsulfonylmethane treatment significantly mitigated PA-induced protein aggregation in human hepatoma HepG2 cells. Additionally, Methylsulfonylmethane treatment reversed the PA-induced impairment of autophagic flux. Methylsulfonylmethane also enhanced the insulin sensitivity and significantly suppressed the HFD-induced obesity and hepatic steatosis in mice. Western blotting revealed that Methylsulfonylmethane improved ubiquitinated protein clearance in HFD-induced fatty liver. Remarkably, Methylsulfonylmethane promoted the activation of AMPK and ULK1 and inhibited mTOR activity. Conclusion: Our study suggests that MSM ameliorates hepatic steatosis by enhancing the autophagic flux via an AMPK/mTOR/ULK1-dependent signaling pathway. These findings highlight the therapeutic potential of MSM for obesity-related MAFLD treatment.

Keywords: AMPK/mTOR; ULK1; autophagy; methylsulfonylmethane; obesity.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2023R1A2C1005469, NRF-2017R1A6A1A03015713, and NRF-2020R1A2C1102244).