肝窦内皮细胞通过USP12/CD36轴调控肝脏炎症和脂质代谢，该轴是雷公藤红素治疗的靶点
Sinusoidal endothelial cells orchestrate liver inflammation and lipid metabolism via USP12/CD36 axis being the target of celastrol therapy.
摘要(中文译文)
脂质代谢紊乱和炎症是代谢功能障碍相关脂肪性肝炎(MASH)的标志性特征,即使在非肥胖状态下也构成重大的治疗挑战,因此发现新的致病机制和治疗方法势在必行。尽管雷公藤红素(Celastrol,Cel)能显著改善高脂饮食(HFD)诱导的肥胖,但其是否以及通过何种分子基础直接改善肝脏炎症和脂质代谢紊乱仍不清楚。在此,我们利用胆碱缺乏、L-氨基酸限定、高脂饮食(CDAHFD)诱导的MASH模型,证明Cel可改善脂肪性肝炎,并鉴定出肝窦内皮细胞(LSECs)——肝脏免疫代谢稳态的关键守门人——中的CD36是协调肝脏脂质转运和炎症反应的核心介质。在阐明调控机制方面,我们发现USP12去除CD36上的K48连接泛素化并在LSECs中稳定CD36。Cel下调USP12,从而促进CD36泛素化及随后的降解,进而减弱趋化因子驱动的巨噬细胞募集并抑制病理性脂质转运。该轴线的临床相关性得到了人脂肪性肝炎肝脏中USP12和CD36同时上调的支持。这些发现揭示了LSEC异质性通过USP12/CD36轴线协调肝脏代谢和炎症,将其确定为如Cel等药物干预的治疗靶点。
Abstract
Disordered lipid metabolism and inflammation, the hallmark features of metabolic dysfunction-associated steatohepatitis (MASH), present a significant therapeutic challenge even in the absence of obesity, making the discovery of novel pathogenic mechanisms and therapies imperative. Although Celastrol (Cel) markedly ameliorates high-fat diet (HFD)-induced obesity, whether and by what molecular basis it directly ameliorates hepatic inflammation and disordered lipid metabolism remains unclear. Here, using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASH model, we demonstrate that Cel ameliorates steatohepatitis and identify CD36 in liver sinusoidal endothelial cells (LSECs)-the key gatekeepers of hepatic immunometabolic homeostasis-as the central mediator coordinating hepatic lipid transport and inflammatory responses. Elucidating the regulatory mechanism, we found that USP12 removes K48-linked ubiquitination from CD36 and stabilizes it in LSECs. Cel downregulates USP12, thereby promoting CD36 ubiquitination and subsequent degradation, which in turn attenuates chemokine-driven macrophage recruitment and suppresses pathological lipid transport. The clinical relevance of this axis is supported by the concurrent upregulation of both USP12 and CD36 in human livers with steatohepatitis. These findings reveal that LSEC heterogeneity orchestrates hepatic metabolism and inflammation via the USP12/CD36 axis, designating it a therapeutic target for interventions with agents such as Cel.
如何引用
AMA
Hu Hua, Wenping Zhu, Le Sun, Ying Ren, Juanjuan Li, Lv Jin, et al. Sinusoidal endothelial cells orchestrate liver inflammation and lipid metabolism via USP12/CD36 axis being the target of celastrol therapy.. Biochimica et biophysica acta. Molecular basis of disease. 2027; doi:10.1016/j.bbadis.2026.168454.
APA
Hu Hua, Wenping Zhu, Le Sun, Ying Ren, Juanjuan Li, Lv Jin, et al (2027). Sinusoidal endothelial cells orchestrate liver inflammation and lipid metabolism via USP12/CD36 axis being the target of celastrol therapy.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168454
GB/T 7714
Hu Hua, Wenping Zhu, Le Sun, Ying Ren, Juanjuan Li, Lv Jin, et al. Sinusoidal endothelial cells orchestrate liver inflammation and lipid metabolism via USP12/CD36 axis being the target of celastrol therapy.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2027 doi:10.1016/j.bbadis.2026.168454.
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