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Selenoprotein K-dependent MyD88 palmitoylation promotes hepatic metaflammation in high-fat diet fed mice
Mengyue You1, Yun Zhang2, Meilin Gao2
1Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China; Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China.
Abstract:
Metaflammation is characteristic of chronic metabolic inflammation, associated with increased risk of development of metabolic dysfunction-associated steatotic liver disease (MASLD). Palmitoylation of Myeloid differentiation factor 88 (MyD88) adaptor protein mediates biologically important signal transduction pathways in inflammatory responses. However, the molecular mechanisms underlying MyD88 palmitoylation contributes to lipid-induced metaflammation in the progression of MASLD is not completely understood. In this study, an increment of MyD88 palmitoylation was observed in the livers of high-fat diet fed mice, accompanied by increased lipid accumulation and an inflammatory response. Inhibition of MyD88 palmitoylation attenuated the inflammation and hepatic steatosis in HFD-induced mice. Mechanistically, palmitoylation of MyD88 activated NF-κB-p65 and p38 MAPK signals in a selenoprotein K (SelK)-DHHC6 palmitoyltransferase complex dependent pathway. Intervention of SelK SH3 binding domain reduced the palmitoylation level of MyD88 by inhibiting the interaction between SelK and DHHC6. Our findings suggest that MyD88 palmitoylation regulates the metabolic disorder and metaflammation through SelK/DHHC6-dependent pathway, cooperatively. Inhibition of MyD88 palmitoylation and SelK SH3 binding domain may represent a new therapeutic strategy for treatment of MASLD progression.
Insights
Myeloid differentiation factor 88 (MyD88) palmitoylation drives lipid-induced inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD). Inhibiting this process, via SelK/DHHC6, offers a potential therapeutic strategy for MASLD.
Area of Science:
- Biochemistry
- Cell Biology
- Hepatology
Background:
- Metaflammation, a chronic metabolic inflammation, is linked to increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD).
- Myeloid differentiation factor 88 (MyD88) adaptor protein palmitoylation is crucial for inflammatory signal transduction, but its role in MASLD is unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which MyD88 palmitoylation contributes to lipid-induced metaflammation in MASLD progression.
- To investigate the potential of targeting MyD88 palmitoylation as a therapeutic strategy for MASLD.
Main Methods:
- Utilized high-fat diet (HFD) induced mouse models to study liver inflammation and steatosis.
- Investigated the role of selenoprotein K (SelK) and DHHC6 palmitoyltransferase in MyD88 palmitoylation.
- Examined the activation of NF-κB-p65 and p38 MAPK signaling pathways.
Main Results:
- Increased MyD88 palmitoylation, lipid accumulation, and inflammation were observed in HFD-fed mice.
- Inhibition of MyD88 palmitoylation reduced inflammation and hepatic steatosis in HFD-induced mice.
- MyD88 palmitoylation activated NF-κB-p65 and p38 MAPK via a SelK-DHHC6 complex; SelK SH3 domain intervention reduced MyD88 palmitoylation.
Conclusions:
- MyD88 palmitoylation, regulated by the SelK/DHHC6 pathway, promotes metabolic dysfunction and metaflammation in MASLD.
- Inhibiting MyD88 palmitoylation or the SelK SH3 binding domain presents a novel therapeutic avenue for MASLD treatment.
