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宋保亮(Bao-Liang Song)
时间:2016-12-26 10:53:43 阅读量:

Appointment: Professor, Dean
Department: Biochemistry
Research: Cholesterol metabolism and metabolic diseases
Location: College of Life Sciences, Room 1134
Email: blsong@whu.edu.cn


1993-1997 南京大学生物科学与技术系,学士
      B.S. Biology, Nanjing University, Nanjing, China
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
      Ph.D. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological
      Sciences, Chinese Academy of Sciences. 博士

工作经历与任职/Professional Experience
2002-2005  美国德克萨斯大学西南医学中心,博士后
       Post-doctoral research fellow, UT Southwestern Medical Center, Mentors: Drs. Mike
       Brown, Joe Goldstein, Russell DeBose-Boyd

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。
       Principle Investigator, Institute of Biochemistry and Cell Biology, Shanghai Institutes
       for Biological Sciences, Chinese Academy of Sciences.

2014-至今  体球网,教授,院长
       Professor and Dean, College of Life Sciences, Wuhan University, Wuhan, China

2010-至今  J. of Molecular Cell Biology, Associate Editor
2012-至今  J. Biol. Chem., Editorial Board Member
2014-2016  International Conference on the Bioscience of Lipids (ICBL) 筹划委员
2018-至今  国家基金委“糖脂代谢的时空网络调控”重大研究计划专家组组长
2019-至今  中国细胞生物学会,副理事长

亚太Arthur Kornberg Memorial Award(2013)

研究概述/Research Description
  胆固醇是生命活动必需的脂类物质,并与心脑血管疾病、神经退行性疾病及肿瘤等的发生密切相关,胆固醇代谢是生物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)阐明一个胆固醇合成的负反馈调控通路与人体胆固醇吸收的分子通路,奠定了当前学术界对这两个代谢途径的认识;2)发现由溶酶体-过氧化物酶体膜接触介导的胆固醇运输新途径,证明膜接触是主要的运输方式,并决定脂质在细胞内的精确分布;3)鉴定蛋白质胆固醇共价修饰新类型,颠覆了20多年来认为Hedgehog是唯一胆固醇修饰蛋白的认识,揭示胆固醇可作为共价配体调控信号转导和发育。以通讯(含共同通讯)作者发表论文30余篇,包括1篇Science、1篇Cell、1篇Nature Medicine、4篇Cell Metabolism、1篇Nature Cell Biology、1篇Molecular Cell、1篇Nature Metabolism。成果被选入十余部英文教材与专著。

Cholesterol is an essential component of mammalian membranes. But high level of circulating cholesterol causes cardiovascular disease. Imbalanced cholesterol metabolism is related to Alzheimer’s disease, cancer and other diseases. Aiming to address fundamental questions in the lipid field and improve human health, we focus on cholesterol metabolism and have made scientific achievements as follows.

1. Regulation of cholesterol biosynthesis and intestinal absorption.
We identify a rare frameshift variant in the LIMA1 gene from a Chinese Kazakh family with inherited low plasma cholesterol. The loss-of-function mutation of LIMA1 reduces intestinal cholesterol absorption and lower plasma cholesterol, suggesting targeting LIMA1 can be a new way to lower cholesterol level (Science, 2018). (B) We have elucidated the molecular mechanism of intestinal cholesterol absorption. We find that NPC1L1 and Flotillins form cholesterol-rich microdomains in the plasma membrane (PNAS, 2011). When the cholesterol level is high, cholesterol binds to the N-terminal domain of NPC1L1 (JBC, 2011), releasing its C-terminal cytoplasmic tail to recruit the clathrin adaptor Numb and initiating clathrin-mediated endocytosis (Nat Med, 2014). The cholesterol absorption inhibitor ezetimibe blocks cholesterol uptake by impairing NPC1L1 endocytosis (Cell Metab, 2008). Cholesterol and fatty acids stabilize ACAT-2 that increases cholesterol absorption efficiency and prevents lipotoxicity (NCB, 2017). (C) The sterol-regulated degradation of HMG-CoA reductase (HMGCR) and the SREBP pathway are two major feedback regulatory mechanisms governing cholesterol synthesis. Together with others, we have delineated the HMGCR degradation pathway. We identify gp78 and RNF145 as the key E3s catalyzing HMGCR ubiquitination (Mol Cell, 2005; Cell Metab, 2012; JBC, 2018), characterized lanosterol, 24,25-dihydrolanosterol and geranylgeraniol as the endogenous regulators (JBC, 2003; Cell Metab, 2005), reveal that Ufd1 is a cofactor of gp78 (Cell Metab, 2007). (D) Based on these findings, we have developed compounds to treat hyperlipidemia by inhibiting SREBP processing or inducing HMGCR degradation (Cell Metab, 2011; Nat Commun, 2018).

2. Cholesterol transport through lysosome-peroxisome membrane contacts.
Most mammalian cells take up cholesterol from low-density lipoprotein (LDL) through receptor-mediated endocytosis. After reaching lysosomes, LDL-derived cholesterol continues to move to other organelles. However, to where and how cholesterol moves from lysosome are poorly understood. We find that cholesterol can be conveyed through membrane contact sites formed between lysosomal protein synaptotagmin VII (Syt7) and peroxisomal lipid PI(4,5)P2 (Cell, 2015). We further identify that the GARP complex is involved in cholesterol transport by targeting NPC2 to lysosomes (Cell Rep, 2017). We have reviewed the cholesterol transport at membrane contact sites (TiBS, 2018).

3. Covalent cholesterol modification of Smoothened (SMO).
Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of SMO. Through an unbiased biochemical screen, we identify that SMO is covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification is inhibited by Patched-1 (Ptch1) but enhanced by Hh. The cholesterylation of SMO is critical for Hh signal transduction, assuring proper embryonic development (Mol Cell, 2017). This work reveals a novel function of cholesterol as a covalent ligand of SMO to regulate cell fate.

Our long-term goal is to reveal the mechanisms of cholesterol metabolism and develop novel strategies to treat cholesterol-related diseases.

            Figure 1. Summary of Song’s work on cholesterol metabolism.

Representative Publications (#: Co-first; *: Co-corresponding): 

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, https://doi.org/10.1038/s41586-020-2928-y, 2020

2) Luo J, Yang H and
Song BL*. Mechanisms and regulation of cholesterol homeostasis. Nature Reviews Molecular Cell Biology. 21(4): 225-245, 2020

3) 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. Sci China Life Sci., 62(9):1117-1135, 2019

4) 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: 570-583, 2019

5) 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

6) 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

7) 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: 154-162, 2017

8) 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

9) 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  

10) 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: 213-225, 2012  

11) 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: 44-56, 2011

12) 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: 508-519, 2008

13) 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, 6:115-128, 2007

14) Ge L, Qi W, Wang LJ, Miao HH, Qu YX, Li BL and
Song BL*. Flotillins play an essential role in Niemann-Pick C1 Like 1-mediated cholesterol uptake. PNAS, 108(2): 551-6, 2011

Song BL, Sever N, and DeBose-Boyd RA*. Gp78, a membrane anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Molecular Cell. 19(6):829-840, 2005

Song BL, Javitt NB, and DeBose-Boyd RA*. Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol. Cell Metabolism, 1: 179-189, 2005

17) Sever N#,
Song BL#, Yabe D#, Goldstein JL*, Brown MS*, and DeBose-Boyd RA. Insig-dependent ubiquitination and degradation of mammalian 3-Hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J Biol Chem, 278: 52479-52490, 2003