肝脂肪素-2 通过 Nedd4-1-SR-BI 轴控制小鼠的 HDL 代谢和动脉粥样硬化。

Hepatocytic lipocalin-2 controls HDL metabolism and atherosclerosis via Nedd4-1-SR-BI axis in mice.

机构信息

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.

出版信息

Dev Cell. 2023 Nov 6;58(21):2326-2337.e5. doi: 10.1016/j.devcel.2023.09.007. Epub 2023 Oct 19.

DOI:10.1016/j.devcel.2023.09.007

PMID:37863040

Abstract

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.

摘要

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。