Le May Cédric, Ducheix Simon, Cariou Bertrand, Rimbert Antoine
Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France.
Curr Atheroscler Rep. 2025 Jan 11;27(1):26. doi: 10.1007/s11883-024-01264-w.
While lipid-lowering therapies demonstrate efficacy, many patients still contend with significant residual risk of atherosclerotic cardiovascular diseases (ASCVD). The intestine plays a pivotal role in regulating circulating lipoproteins levels, thereby exerting influence on ASCVD pathogenesis. This review underscores recent genetic findings from the last six years that delineate new biological pathways and actors in the intestine which regulate lipid-related ASCVD risk.
Specifically, we detail the role of LIMA1 in cholesterol absorption within enterocytes, the function of PLA2G12B in the expansion and lipidation of chylomicrons, the involvement of SURF4 in lipoprotein secretion, and the discovery of a gut-derived hormone named CHOLESIN that modulates cholesterol homeostasis through GPR146 via a gut-liver crosstalk. We further discuss the potential of these newly identified genes and pathways as novel targets for pharmaceutical intervention. Newly identified genetic and intestinal molecular mechanisms offer promising opportunities for preventing and treating ASCVD, but careful evaluation and further research are needed to optimize their clinical application.
尽管降脂疗法已证明具有疗效，但许多患者仍面临动脉粥样硬化性心血管疾病（ASCVD）的显著残余风险。肠道在调节循环脂蛋白水平方面发挥着关键作用，从而对ASCVD的发病机制产生影响。本综述强调了过去六年的最新遗传学研究结果，这些结果描绘了肠道中调节脂质相关ASCVD风险的新生物学途径和作用因素。
具体而言，我们详细阐述了LIMA1在肠细胞内胆固醇吸收中的作用、PLA2G12B在乳糜微粒扩张和脂质化中的功能、SURF4在脂蛋白分泌中的参与，以及发现了一种名为CHOLESIN的肠道衍生激素，它通过肠道-肝脏的串扰，经由GPR146调节胆固醇稳态。我们进一步讨论了这些新发现的基因和途径作为药物干预新靶点的潜力。新发现的遗传和肠道分子机制为预防和治疗ASCVD提供了有前景的机会，但需要仔细评估和进一步研究以优化其临床应用。
