School of Basic Medical Sciences, Fudan University Shanghai, Shanghai 200032, China; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
Dev Cell. 2023 Nov 6;58(21):2326-2337.e5. doi: 10.1016/j.devcel.2023.09.007. Epub 2023 Oct 19.
High-density lipoprotein (HDL) metabolism is regulated by complex interplay between the scavenger receptor group B type 1 (SR-BI) and multiple signaling molecules in the liver. Here, we show that lipocalin-2 (Lcn2) is a key regulator of hepatic SR-BI, HDL metabolism, and atherosclerosis. Overexpression of human Lcn2 in hepatocytes attenuates the development of atherosclerosis via SR-BI in western-diet-fed Ldlr mice, whereas hepatocyte-specific ablation of Lcn2 has the opposite effect. Mechanistically, hepatocyte Lcn2 improves HDL metabolism and alleviates atherogenesis by blocking Nedd4-1-mediated SR-BI ubiquitination at K500 and K508. The Lcn2-improved HDL metabolism is abolished in mice with hepatocyte-specific Nedd4-1 or SR-BI deletion and in SR-BI (K500A/K508A) mutation mice. This study identifies a regulatory axis from Lcn2 to HDL via blocking Nedd4-1-mediated SR-BI ubiquitination and demonstrates that hepatocyte Lcn2 may be a promising target to improve HDL metabolism to treat atherosclerotic cardiovascular diseases.
高密度脂蛋白（HDL）代谢受肝脏中清道夫受体 B 型 1（SR-BI）和多种信号分子之间复杂相互作用的调节。在这里，我们表明，载脂蛋白 L2（Lcn2）是肝脏 SR-BI、HDL 代谢和动脉粥样硬化的关键调节因子。在西方饮食喂养的 Ldlr 小鼠中，肝细胞中高水平的人 Lcn2 通过 SR-BI 可减轻动脉粥样硬化的发展，而肝细胞特异性 Lcn2 缺失则产生相反的效果。从机制上讲，肝细胞 Lcn2 通过阻断 Nedd4-1 介导的 SR-BI 在 K500 和 K508 处的泛素化，改善了 HDL 代谢并减轻了动脉粥样硬化的发生。在肝细胞特异性 Nedd4-1 或 SR-BI 缺失的小鼠以及在 SR-BI（K500A/K508A）突变小鼠中，Lcn2 改善的 HDL 代谢被消除。这项研究确定了一个从 Lcn2 到 HDL 的调节轴，通过阻断 Nedd4-1 介导的 SR-BI 泛素化，并表明肝细胞 Lcn2 可能是改善 HDL 代谢以治疗动脉粥样硬化性心血管疾病的一个有前途的靶点。
