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Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss
Published on: July 19, 2024
Compound J27 alleviates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease by targeting
Jiaxi Ye1, Weiwei Zhu2, Yaqian Cui3
1Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
Background:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most characteristic form of liver diseases. As the member of MAPK family, the cJun-N-terminal-kinase (JNK) plays a crucial role in the pathogenesis of MASLD. A small molecule compound, J27, has demonstrated strong anti-inflammatory effects by inhibiting JNK phosphorylation, but its therapeutic potential in MASLD remains unclear.
Methods:
To evaluate the effect of J27, we used a high-fat diet (HFD)-induced MASLD mouse model with or without J27 treatment. Pathological changes were assessed through tissue staining, biochemical analysis, and other assays. In vitro, J27's effects were tested on macrophages, hepatocytes, and co-culture systems under palmitic acid stimulation.
Results:
J27 significantly reduced HFD-induced hepatic steatosis, liver injury, insulin resistance, and inflammatory responses by targeting JNK both in vivo and in vitro. On one hand, J27 blocked JNK activation, thereby improving insulin signaling and alleviating metabolic dysfunction in hepatocytes. On the other hand, J27 inhibited the inflammatory response in macrophages by disrupting the JNK/NF-κB axis, which, through cell-cell communication, further reduced hepatocyte injury.
Conclusions:
J27, as a potent JNK inhibitor, markedly reduced HFD-induced MASLD, suggesting it as a promising therapeutic candidate for this disease.
Insights
J27, a JNK inhibitor, effectively treats metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing liver fat, injury, and inflammation in mouse models. This compound shows promise as a therapeutic for MASLD.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition.
- cJun-N-terminal-kinase (JNK) signaling is implicated in MASLD pathogenesis.
- The anti-inflammatory compound J27 inhibits JNK phosphorylation, but its MASLD therapeutic potential is unknown.
Purpose of the Study:
- To investigate the therapeutic efficacy of J27 in a high-fat diet-induced MASLD mouse model.
- To elucidate the molecular mechanisms underlying J27's effects on liver steatosis, injury, and inflammation.
- To evaluate J27's impact on JNK signaling in hepatocytes and macrophages.
Main Methods:
- Utilized a high-fat diet (HFD) induced MASLD mouse model with and without J27 treatment.
- Assessed pathological liver changes via tissue staining and biochemical analyses.
- Investigated J27's effects in vitro on macrophages and hepatocytes stimulated with palmitic acid.
Main Results:
- J27 treatment significantly ameliorated HFD-induced hepatic steatosis, liver injury, and insulin resistance.
- J27 inhibited JNK activation, improving insulin signaling in hepatocytes.
- J27 disrupted the JNK/NF-κB axis in macrophages, reducing inflammation and subsequent hepatocyte injury.
Conclusions:
- J27 demonstrates potent JNK inhibitory activity.
- J27 significantly mitigates MASLD progression in a preclinical model.
- J27 is a promising therapeutic candidate for MASLD.
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