宋保亮-细胞稳态湖北省重点实验室

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宋保亮院士、教授

学科专业

生物化学

研究方向

胆固醇代谢与代谢疾病

实验室位置

生科院1134室

联系电话

027-68754157

Email

blsong@whu.edu.cn

学习经历

1997-2002 中科院上海生命科学研究院生物化学与细胞生物学研究所，博士

1993-1997 南京大学生物科学与技术系，学士

主要工作经历与任职情况

2014-至今　武汉大学，教授，

　　　　　　副校长（2022-至今）
　　　　　　生命科学学院院长（2014-至今）
　　　　　　泰康医学院（基础医学院）院长（2022-至今）
　　　　　　泰康生命医学中心主任（2022-至今）

2005-2014 中科院上海生命科学研究院生物化学与细胞生物学研究所

　　　　　　研究组长，研究员，博士生导师

2002-2005 美国德克萨斯大学西南医学中心，博士后

主要社会兼职

2019年-至今中国细胞生物学学会　副理事长

2010年-至今 Journal of Molecular Cell Biology 副主编

2012年-至今 Journal of Biological Chemistry 编委

主要科研奖励和个人荣誉

陈嘉庚青年科学奖（2012）

谈家桢生命科学创新奖（2014）

2015年度中国生命科学领域十大进展（2016）

2020年度中国生命科学领域十大进展（2021）

中国科学院院士（2021）

2022年度中国生命科学领域十大进展（2023）

主持课题项目

1）基金委创新群体，项目名称：脂代谢的稳态调控与重编程，项目起止年月：2021年1月至2025年12月，首席科学家

2）基金委重大研究计划-重点项目“内质网-线粒体-质膜互作对固醇代谢稳态的功能调控”，项目起止年月：2020年1月至2023年12月，负责人

研究概述/Research Description

　　胆固醇是生命活动必需的脂类物质，并与心血管疾病、神经退行性疾病及肿瘤等的发生密切相关，胆固醇代谢是生命医学的前沿领域和药物研发的关键基础。我们长期从事胆固醇代谢研究，取得如下成果：1.阐明小肠胆固醇吸收途径并鉴定一系列蛋白，包括从低血脂家系中发现新调控基因LIMA1。2.阐明一条胆固醇合成负反馈调控途径，即HMGCR降解机制，发现内源信号分子、E3、共因子及营养感知机制，发现USP20是饥饿—进食转化中控制胆固醇合成的关键蛋白。3.发现一细胞内胆固醇运输新途径，即过氧化物酶体—溶酶体—内质网通过膜接触介导转运。4.发现胆固醇共价修饰SMO蛋白，调控信号转导和发育。5.揭示通过抑制糖蛋白受体ASGR1而促进胆固醇外排的通路。这些成果引领胆固醇领域的发展，并对降脂新药研发有重要意义。在Nature (2)、Science、Cell等期刊发表论文60多篇，成果被选入多部经典教材。

Bao-Liang Song’s lab focuses on cholesterol metabolism. 1) He illustrates the molecular pathway of intestinal cholesterol absorption. He finds that NPC1L1 and Flotillins form cholesterol-rich microdomains in the plasma membrane (PM) (PNAS, 2011). Cholesterol binds to the N-terminal domain of NPC1L1, releasing its C-terminal tail from PM and recruiting the clathrin adaptor NUMB to initiate endocytosis (Nature Medicine, 2014). The cholesterol absorption inhibitor ezetimibe blocks cholesterol uptake by impairing NPC1L1 endocytosis (Cell Metab, 2008). He identifies LIMA1 through human genetic study and shows LIMA1 bridges NPC1L1 to Myosin Vb and transports NPC1L1 back to the PM (Science, 2018). 2) He delineates the molecular pathway of sterol-induced degradation of HMGCR, a rate-limiting enzyme in cholesterol biosynthesis. He identifies gp78 and RNF145 as the E3s (Mol Cell, 2005; Cell Metab, 2012), lanosterol as the endogenous regulator (Cell Metab, 2005; Cell Metab, 2011; JLR, 2019) and Ufd1 as a cofactor of gp78 (Cell Metab, 2007). Recently, he finds that USP20 is the key protein controlling cholesterol biosynthesis in the starvation-feeding transition state (Nature, 2020). 3) He finds that cholesterol is transported through lysosome-peroxisome membrane contacts (Cell, 2015). Peroxisomal cholesterol is further delivered to the ER through membrane contacts. 4) He finds that cholesterol covalently modifies the SMO protein through a Ca²⁺-boosted autoreaction, demonstrating cholesterol can function as a covalent ligand to regulate Hedgehog signaling and embryonic development (Mol Cell, 2017; Cell Res, 2022). 5) He recently finds a pathway to promote cholesterol excretion through inhibiting ASGR1 (Nature 2022). His pioneer work has significant impact on the cholesterol field and sheds new light on cholesterol-lowering drug development. As the corresponding author, he has published more than 60 papers including Nature (2), Science, and Cell papers. His work has been included in several classic textbooks such as Lehninger Principles of Biochemistry.

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代表性论文（#并列第一作者，*通讯作者）

Wang JQ, Li LL, Hu A, Deng G, Wei J, Li YF, Liu YB, Lu XY, Qiu ZP, Shi XJ, Zhao X, Luo J and Song BL^*. Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion. Nature, 608(7922):413-420, 2022
Lu XY^#, Shi XJ^#, Hu A^#, Wang JQ^#, Ding Y, Jiang W, Sun M, Zhao X, Luo J, Qi W and Song BL^*. Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis. Nature, 588(7838):479-484, 2020
Zhang YY^#, Fu ZY^#, Wei J^#, Qi W, Baituola G, Luo J, Meng YJ, Guo SY, Yin H, Jiang SY, Li YF, Miao HH, Liu Y, Wang Y, Li BL, Ma YT^*and Song BL^*. A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption. Science, 360(6393):1087-1092, 2018
Chu BB^#, Liao YC^#, Qi W, Xie C, Du X, Wang J, Yang H, Miao HH, Li BL and Song BL^*. Cholesterol transport through lysosome-peroxisome membrane contacts. Cell, 161(2):291-306, 2015
Luo J, Yang H and Song BL^*. Mechanisms and regulation of cholesterol homeostasis. Nature Reviews Molecular Cell Biology, 21(4):225-245, 2020
Gong XM^#, Li YF^#, Luo J^#, Wang JQ^#, Wei J^#, Wang JQ, Xiao T, Xie C, Hong J, Ning G, Shi XJ, Li BL, Qi W^*and Song BL^*. Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance. Nature Metabolism, 1(5):570-583, 2019
Hu A^#, Zhang JZ^#, Wang J, Li CC, Yuan M, Deng G, Lin ZC, Qiu ZP, Liu HY, Wang XW, Wei PC, He X, Zhao X^*, Qiu WW^* and Song BL^*. Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate. Cell Research, 32(3):288-301, 2022
Wang JK, Li Y, Zhao X, Liu YB, Tan J, Xing YY, Adi D, Wang YT, Fu ZY, Ma YT, Liu SM, Liu Y, Wang Y, Shi XJ, Lu XY, Song BL^*and Luo J^*. Ablation of plasma prekallikrein decreases LDL cholesterol by stabilizing LDL receptor and protects against atherosclerosis. Circulation, 145:675-687, 2022
Xiao J, Xiong YN, Yang LT, Wang JQ, Zhou ZM, Dong LW, Shi XJ, Zhao XL, Luo J^* and Song BL^*. POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation. Protein Cell, 12(4):279-296, 2021
Xiao J^#, Luo J^#, Hu A, Xiao T, Li M, Kong Z, Jiang L, Zhou Z, Liao Y, Xie C, Chu B, Miao H, Li B, Shi X and Song BL^*. Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI(4,5)P₂ and extended synaptotagmins. Science China Life Sciences, 62(9):1117-1135, 2019
Wang YJ, Bian Y, Luo J, Lu M, Xiong Y, Guo SY, Yin HY, Lin X, Li Q, Chang CCY, Chang TY, Li BL^*and Song BL^*. Cholesterol and fatty acids regulate cysteine ubiquitination of ACAT2 through competitive oxidation. Nature Cell Biology, 19(7):808-819, 2017
Xiao X^#, Tang JJ^#, Peng C, Wang Y, Fu L, Qiu ZP, Xiong Y, Yang LF, Cui HW, He XL, Yin L, Qi W, Wong CL, Zhao Y, Li BL, Qiu WW^*and Song BL^*. Cholesterol modification of Smoothened is required for hedgehog signaling. Molecular Cell, 66(1):154-162, 2017
Li PS, Fu ZY, Zhang YY, Xu CQ, Ma YT, Li BL and Song BL^*. The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1. Nature Medicine, 20(1):80-86, 2014
Liu TF, Tang JJ, Li PS, Shen Y, Li JG, Miao HH, Li BL^*and Song BL^*. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metabolism, 16(2):213-225, 2012
Tang JJ^#, Li JG^#, Qi W, Qiu WW, Li PS, Li BL and Song BL^*. Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques. Cell Metabolism, 13(1):44-56, 2011
Ge L^#, Wang J^#, Qi W^#, Miao HH, Cao J, Qu YX, Li BL and Song BL^*. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metabolism,7(6):508-519, 2008
Cao J, Wang J, Qi W, Miao HH, DeBose-Boyd RA, Wang J, Li BL^*and Song BL^*. Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism. Cell Metabolism, 6(2):115-128, 2007

职称	院士、教授	学科专业	生物化学
研究方向	胆固醇代谢与代谢疾病	实验室位置	生科院1134室
联系电话	027-68754157	Email	blsong@whu.edu.cn