Palmitoylation of PKC by ZDHHC5 in hypothalamic microglia presents as a therapeutic target for fatty liver disease

THERANOSTICS(2024)

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摘要
The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high -fat diet -induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin -labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase C6 (PKC delta). Importantly, ART directly targeted PKC delta to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKC delta knockdown markedly impaired ART -dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single -cell transcriptomics analysis in human brain tissues revealed that the level of PKC delta in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKC delta in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus -liver communication, and provides a promising therapeutic target for fatty liver diseases.
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关键词
hepatic lipid metabolism,protein kinase C delta (PKC delta),palmitoylation modification,hypothalamic microglia,artemether
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