Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia

Chao Xue¹, Peng Zeng², Ke Gong³, Qian Li², Zian Feng⁴, Mengyao Wang³, Shasha Chen³, Yanfang Yang², Jiaqi Li², Shuang Zhang³, Zequn Yin⁴, Yingquan Liang³, Tengteng Yan³, Miao Yu⁵, Ke Feng², Dan Zhao², Xiaoxiao Yang³, Xia Zhang⁶, Likun Ma⁴, Yasuko Iwakiri⁷, Liang Chen⁸, Xiaoqiang Tang⁹, Yuanli Chen¹⁰, Houzao Chen¹¹, Yajun Duan¹²

Affiliations

¹ Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China; College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
² College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
³ Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China.
⁴ Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
⁵ Medical College of Soochow University, Suzhou 215031, China.
⁶ Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin 301800, China.
⁷ Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06519, USA.
⁸ College of Life Science, Anhui Medical University, Hefei 230032, China.
⁹ Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, No. 17 People’s South Road, Chengdu, Sichuan 610041, China.
¹⁰ Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address: chenyuanli@hfut.edu.cn.
¹¹ Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China. Electronic address: chenhouzao@ibms.cams.cn.
¹² Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China. Electronic address: yajunduan@ustc.edu.cn.

PMID: 39235944
DOI: 10.1016/j.celrep.2024.114691

Free article

Abstract

The strategy of lowering cholesterol levels by promoting cholesterol excretion is still lacking, and few molecular targets act on multiple cholesterol metabolic processes. In this study, we find that Nogo-B deficiency/inhibition simultaneously promotes hepatic uptake of cholesterol and cholesterol excretion. Nogo-B deficiency decreases cholesterol levels by activating ATP-binding cassette transporters (ABCs), apolipoprotein E (ApoE), and low-density lipoprotein receptor (LDLR) expression. We discover that Nogo-B interacts with liver X receptor α (LXRα), and Nogo-B deficiency inhibits ubiquitination degradation of LXRα, thereby enhancing its function on cholesterol excretion. Decreased cellular cholesterol levels further activate SREBP2 and LDLR expression, thereby promoting hepatic uptake of cholesterol. Nogo-B inhibition decreases atherosclerotic plaques and cholesterol levels in mice, and Nogo-B levels are correlated to cholesterol levels in human plasma. In this study, Nogo-B deficiency/inhibition not only promotes hepatic uptake of blood cholesterol but also facilitates cholesterol excretion. This study reports a strategy to lower cholesterol levels by inhibiting Nogo-B expression to promote hepatic cholesterol uptake and cholesterol excretion.

Keywords: CP: Metabolism; LXRα; Nogo-B; atherosclerosis; cholesterol metabolism; coronary heart disease; hypercholesterolemia.

Cell Rep. 2024 Sep 24;43(9):114691.doi: 10.1016/j.celrep.2024.114691. Epub 2024 Sep 3. (IF:8.8).

Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia

Abstract

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