Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation.
Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation.
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DOI：
10.1016/j.metabol.2023.155774
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发表时间：
2024-01
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通讯作者：
Zhenmei Chen;Wei-qing Shao;Yitong Li;Xiandi Zhang;Yan Geng;Xiaochen Ma;Baorui Tao;Yue Ma;Chenhe Yi;Bo Zhang;Rui Zhang;Jing Lin;Jinhong Chen
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作者：
Zhenmei Chen;Wei-qing Shao;Yitong Li;Xiandi Zhang;Yan Geng;Xiaochen Ma;Baorui Tao;Yue Ma;Chenhe Yi;Bo Zhang;Rui Zhang;Jing Lin;Jinhong Chen
背景与目的胆固醇代谢异常是导致胆固醇结石的主要因素。枯草杆菌前蛋白转换酶9(PCSK9)在胆固醇稳态中起关键作用，其抑制剂已被批准用于治疗各种胆固醇代谢紊乱，如高胆固醇血症和心血管疾病，但其在CGS中的作用尚不清楚。本研究旨在阐明PCSK9促进CGS形成的机制，并探讨PCSK9抑制剂alirocumab在防治CGS中的应用。方法与结果CGS患者血清、胆汁和肝组织中PCSK9的表达明显高于无胆结石患者。此外，在CGS患者中，肝脏PCSK9与肝脏胆固醇呈正相关，与肝胆汁酸(BAS)呈负相关，提示PCSK9参与了与CGS相关的肝脏胆固醇代谢紊乱。机制上，体外实验表明，抑制PCSK9通过减少其溶酶体的降解而增强其α的核表达，从而激活细胞色素P7A1的转录。最后，抑制PCSK9通过PPARα介导的细胞色素P7A1活化促进胆固醇向BAS的转化，从而阻止了CGS的形成，并溶解了CGS小鼠中现有的结石。结论抑制PCSK9可能通过激活PPARα介导的细胞色素P7A1的表达，促进胆固醇转化为BAS而发挥防治作用，这凸显了抑制PCSK9作为预防和治疗CGS的一种有希望的临床应用的可能性。我们的研究观察到，抑制PCSK9通过激活PPARα介导的CYP7A1表达和促进胆固醇转化为BAs来预防和溶解CGS。在机制上，抑制PCSK9通过抑制其溶酶体的降解而增强其α的核表达，进而激活其转录。我们的研究揭示了PCSK9在CGS中的新功能和新机制，为CGS提供了一个具有潜在临床应用的新的预防和治疗靶点。
Background & aimsDysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS.Approach & resultsThe expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors.ConclusionsInhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications.Impact and implicationsPCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications.