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

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

  • Dev Cell. 2023 Oct 18:S1534-5807(23)00494-X. doi: 10.1016/j.devcel.2023.09.007.
Shuwei Hu 1,  Yingdong Zhu 2,  Xiaojie Zhao 3,  Rui Li 3,  Guangze Shao 3,  Dongxu Gong 3,  Chencheng Hu 3,  Hongjun Liu 3,  Kexin Xu 4,  Chenxi Liu 3,  Minghuan Xu 3,  Zhonghua Zhao 3,  Tao Li 5,  Zhigang Hu 6,  Mengle Shao 7,  Jun- Liu 4,  Xinwei Li 8,  Huijuan Wu 3,  Jing Li 9,  Yanyong Xu 10
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Fudan University Shanghai, Shanghai 200032, China; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
  • 2 Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
  • 3 Department of Pathology, School of Basic Medical Sciences, Fudan University Shanghai, Shanghai 200032, China.
  • 4 Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 5 Department of Hepatobiliary Surgery, Peking University People's Hospital Xizhimen South Street, West District, Beijing 100044, China.
  • 6 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
  • 7 Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
  • 8 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China.
  • 9 Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China. Electronic address: s-a-sally@163.com.
  • 10 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Frontier Innovation Center, Fudan University Shanghai, Shanghai 200032, China; Diabetes, Obesity and Metabolism Research Center, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA. Electronic address: yanyong_xu@fudan.edu.cn.
PMID: 37863040 DOI: 10.1016/j.devcel.2023.09.007
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.

Keywords

HDL metabolism; Lcn2; SR-BI ubiquitination; atherosclerosis.

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