Sappanone A alleviates metabolic dysfunction-associated steatohepatitis by decreasing hepatocyte lipotoxicity via targeting Mup3 in mice

An Zhu; Xueqing Yan; Mengting Chen; Yifan Lin; Lanqian Li; Yufei Wang; Jiabin Huang; Jiale He; Mengchen Yang; Wenxi Hua; Kunqi Chen; Jing Qi; Zixiong Zhou

doi:10.1016/j.phymed.2024.156341

Sappanone A alleviates metabolic dysfunction-associated steatohepatitis by decreasing hepatocyte lipotoxicity via targeting Mup3 in mice

Phytomedicine. 2024 Dec 20:136:156341. doi: 10.1016/j.phymed.2024.156341. Online ahead of print.

Authors

An Zhu¹, Xueqing Yan², Mengting Chen¹, Yifan Lin¹, Lanqian Li³, Yufei Wang², Jiabin Huang³, Jiale He³, Mengchen Yang³, Wenxi Hua³, Kunqi Chen⁴, Jing Qi⁵, Zixiong Zhou⁶

Affiliations

¹ Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, 1 Xue Fu North Road, Fuzhou 350122, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, No.1, Xuefu North Road, University Town, Fuzhou, Fujian 350122, China.
³ Department of Pathology & Diagnosis Pathological Center, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China.
⁴ Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, 1 Xue Fu North Road, Fuzhou 350122, China. Electronic address: kunqi.chen@fjmu.edu.cn.
⁵ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, No.1, Xuefu North Road, University Town, Fuzhou, Fujian 350122, China. Electronic address: qijing2020@fjmu.edu.cn.
⁶ Department of Pathology & Diagnosis Pathological Center, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China. Electronic address: zzxpathology@fjmu.edu.cn.

PMID: 39733550
DOI: 10.1016/j.phymed.2024.156341

Abstract

Background and purpose: Metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory lipotoxic disorder marked by hepatic steatosis, hepatocyte damage, inflammation, and varying stages of fibrosis. Sappanone A (SA), a flavonoid, exhibits anti-inflammatory and hepatoprotection activities. Nevertheless, the effects of SA on MASH remain ambiguous. We evaluated the effects of SA on hepatocyte lipotoxicity, inflammation, and fibrosis conditions in MASH mice, as well as the underlying mechanisms.

Methods: A conventional murine MASH model fed a methionine-choline-deficient (MCD) diet was utilized to assess the role of SA on MASH in vivo. Drug target prediction and liver transcriptomics were employed to elucidate the potential actions of SA. AML12 cells were applied to further explore the effects and mechanisms of SA in vitro.

Results: The in silico prediction indicated that SA could modulate inflammation, insulin resistance, lipid metabolism, and collagen catabolic process. Treating with SA dose-dependently lessened the elevated levels of serum ALT and AST in mice with diet-triggered MASH, and high-dose SA treatment exhibited a similar effect to silymarin. Additionally, SA treatment significantly reduced lipid deposition, inflammation, and fibrosis subjected to metabolic stress in a dose-dependent manner. Besides, SA mitigated palmitate-triggered lipotoxicity in hepatocytes. Liver transcriptomics further confirmed the aforementioned findings. Of note, mRNA-sequencing analysis and molecular biology experiments demonstrated that SA statistically up-regulated the hepatic expression of major urinary protein 3 (Mup3), thereby facilitating lipid transportation and inhibiting lipotoxicity. Furthermore, Mup3 knockdown in hepatocytes significantly abolished the hepatoprotection provided by SA.

Conclusion: SA alleviates MASH by decreasing lipid accumulation and lipotoxicity in hepatocytes, at least partially by targeting Mup3, and subsequently blocks MASH process. Therefore, SA could be a promising hepatoprotective agent in the context of MASH.

Keywords: Hepatocyte; Lipotoxicity; MASH; Mup3; Sappanone A.