Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia.

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-09-03 DOI:10.1016/j.celrep.2024.114691

Chao Xue, Peng Zeng, Ke Gong, Qian Li, Zian Feng, Mengyao Wang, Shasha Chen, Yanfang Yang, Jiaqi Li, Shuang Zhang, Zequn Yin, Yingquan Liang, Tengteng Yan, Miao Yu, Ke Feng, Dan Zhao, Xiaoxiao Yang, Xia Zhang, Likun Ma, Yasuko Iwakiri, Liang Chen, Xiaoqiang Tang, Yuanli Chen, Houzao Chen, Yajun Duan

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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.

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抑制 Nogo-B 可促进胆固醇代谢，从而降低高胆固醇血症。

目前仍缺乏通过促进胆固醇排泄来降低胆固醇水平的策略，而且很少有分子靶点作用于多个胆固醇代谢过程。本研究发现，Nogo-B 缺乏/抑制可同时促进肝脏摄取胆固醇和排泄胆固醇。Nogo-B 缺乏会激活 ATP 结合盒转运体（ABC）、载脂蛋白 E（ApoE）和低密度脂蛋白受体（LDLR）的表达，从而降低胆固醇水平。我们发现，Nogo-B 与肝 X 受体α（LXRα）相互作用，Nogo-B 缺乏会抑制 LXRα 的泛素化降解，从而增强其排泄胆固醇的功能。细胞胆固醇水平的降低会进一步激活 SREBP2 和 LDLR 的表达，从而促进肝脏对胆固醇的吸收。抑制 Nogo-B 可降低小鼠动脉粥样硬化斑块和胆固醇水平，Nogo-B 水平与人体血浆中的胆固醇水平相关。在这项研究中，Nogo-B 缺乏/抑制不仅能促进肝脏吸收血液中的胆固醇，还能促进胆固醇的排泄。本研究报告了一种通过抑制 Nogo-B 表达来促进肝脏胆固醇摄取和胆固醇排泄，从而降低胆固醇水平的策略。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.