王琰武汉大学生命科学学院,武汉 430072

编委: 黄勋
收稿日期:2020-11-11修回日期:2020-11-12网络出版日期:2020-11-20

Received:2020-11-11Revised:2020-11-12Online:2020-11-20
作者简介 About authors
王琰,博士,教授,研究方向：人类遗传与脂质代谢。E-mail:Wang.y@whu.edu.cn。




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王琰. 抑制胆固醇合成促进能量消耗并改善代谢综合征. 遗传[J], 2020, 42(11): 1039-1041 doi:10.16288/j.yczz.20-378


生命活动是由一系列复杂有序的化学反应构成,生命活动的维持需要抵抗系统性的熵增趋势,可以说生命以“负熵”为生！所有生命体都需要持续从外界获取能量与营养物质进行做功,而能量与营养物质的供给具有时间与空间限制。在漫长的演化过程中,生命体进化出精细的分子机制,以感知机体能量与营养物质状态,调节体内能量物质的储存与利用。动物体内,糖原和甘油三酯是两大类主要的能量储存形式。进食等能量充足状态促进胰岛素的分泌,抑制胰高血糖素的分泌,从而促进糖原与脂质的合成。而饥饿等能量缺乏状态抑制胰岛素的分泌,促进胰高血糖素的增加,从而促进糖原与脂质的水解与氧化^[1]。

胆固醇是生命体重要的结构与信号分子,是细胞增殖与维持其生命活动的基本元件,几乎所有细胞都具有合成胆固醇的能力。人体所需胆固醇中,约1/3从食物中摄取,2/3依靠内源合成,其中肝脏是胆固醇合成最主要器官。3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMGCR)是胆固醇合成限速酶。当外源胆固醇摄取不足时,一方面激活胆固醇调节元件结合蛋2 (SREBP2)的转录活性,增加胆固醇合成通路相关基因的转录表达,同时增强HMGCR蛋白质的稳定性,进而增加机体内源胆固醇的合成;而当外源胆固醇摄取过量时,会抑制SREBP2通路的转录活性,并促进泛素连接酶gp78介导的HMGCR泛素化降解,降低内源胆固醇的合成^[2]。胆固醇的这一负反馈调节通路对维持机体胆固醇水平至关重要(图1)。

胆固醇的合成涉及30余步化学反应,是一个高耗能过程。因此饥饿等能量缺乏状态抑制内源胆固醇的合成,而进食等能量充足状态激活其内源合成。机体感知营养与能量状态,调节葡萄糖与甘油三酯储存与利用的分子机制已有深入研究,而机体如何感知营养与能量状态,进而调节胆固醇合成的分子机制尚不清楚。2020年11月11日,武汉大学宋保亮课题组的研究结果首次揭示了肝脏感知胰岛素和葡萄糖信号,通过mTORC1-USP20信号通路,促进HMGCR的去泛素化而提高其稳定性,进而增加胆固醇合成的作用机制。抑制该通路导致机体能量损耗,以产热形式释放,抵抗食物诱导的体重增加,改善血脂、胰岛素敏感性等代谢综合征表型,为该类疾病的治疗提供了新的重要思路^[3]。

该项研究起始于一个日常现象,即进食后胆固醇合成显著提高。他们发现进食主要增加胆固醇合成限速酶HMGCR的蛋白质水平,随后研究发现进食后的肝脏裂解液能够降低HMGCR的泛素化水平,表明肝脏中存在HMGCR的去泛素化酶。通过筛选所有已知去泛素化酶,发现USP20是唯一能够作用于HMGCR的去泛素化酶。在肝脏特异性USP20的基因敲除小鼠中,进食诱导的HMGCR蛋白水平的增加被完全抑制,同时进食后胆固醇的合成也显著下降,表明USP20是调节进食后胆固醇合成的重要分子。

该研究进一步通过精细的生化手段证明,进食通过Insulin-AKT, Glucose-AMPK信号通路协同激活mTORC1的活性,促进USP20第132位和134位丝氨酸的磷酸化,从而促进USP20与HMGCR复合体的形成,降低HMGCR的泛素化水平,从而增加HMGCR蛋白水平,促进胆固醇合成。去泛素化酶USP20与HMGCR的相互作用需要泛素化酶gp78的参与,而后者在胆固醇负反馈调节HMGCR泛素化降解过程中发挥关键作用^[4]。这一结果表明gp78与USP20这一对泛素化酶和去泛素化酶是机体感知不同能量与营养物质状态,调控胆固醇合成的核心元件(图1)。有趣的是,该研究还发现抑制USP20的活性在导致胆固醇合成下降的同时,促进胆固醇合成中间物3-羟基-3-甲基戊二酸单酰辅酶A (HMG- CoA)向琥珀酸的转化,进而增加机体能量消耗与产热,抵抗食物诱导的体重增加,改善机体的糖耐受与胰岛素敏感性、降低血脂,为高血脂、糖尿病的治疗提供了新的重要思路。利用HMGCR(K248R) 基因定点突变(Knock-in)小鼠,他们证明这些代谢表型的改善完全依赖于对HMGCR的调节,表明USP20主要通过HMGCR调节胆固醇合成与能量代谢平衡。

图1

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图1SCAP-SREBP2通路介导的胆固醇负反馈调节与mTORC1-USP20通路介导的胰岛素与葡萄糖感知共同调节机体胆固醇合成

甾醇类物质通过抑制SREBP切割活化蛋白(SCAP)与SREBP2复合体向高尔基的转运抑制SREBP2的转录活性,同时促进gp78依赖的HMGCR的泛素化降解,从而抑制胆固醇的合成。细胞通过mTORC1复合体感知机体胰岛素与葡萄糖状态,通过USP20增加HMGCR蛋白质稳定性,进而促进胆固醇的合成。SRE：甾醇响应原件;LDLR：低密度脂蛋白受体。
Fig. 1Cholesterol synthesis is regulated by both SCAP-SREBP2 pathway-mediated sterols sensing and mTORC1-USP20 pathway-mediated insulin and glucose sensing



胆固醇吸收(NPC1L1, LIMA1)^[5,6]、运输(ApoB, LDLR, ARH, PCSK9)^[1,7~9]、合成(HMGCR, GPR146) ^[1,10,11]与外排(ABCG5/ABCG8)^[12]相关基因或基因组位点的遗传突变均能导致胆固醇代谢异常。针对NPC1L1的抑制剂Ezetimibe^[13],PCSK9的抑制性抗体^[14,15],HMGCR的抑制剂他汀类药物^[16]已成为治疗各类高胆固醇血症和心脑血管疾病的一线临床用药。该项研究首次将胆固醇合成调节与能量代谢平衡联系起来,不仅揭示了机体感知能量与营养状态,调节胆固醇合成的分子机制,也为肥胖、高血脂、糖尿病等疾病的治疗提供了新的视角。尤为重要的是,针对USP20的抑制剂(GSK2643943A)在小鼠中显著降低进食后胆固醇合成与高脂食物诱导的体重增加,同时具有提高机体胰岛素敏感性、改善代谢综合征等治疗效果,为后续药物研发提供重要理论依据。

参考文献 View Option 原文顺序
文献年度倒序
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被引期刊影响因子

[1] Chen LG, Chen XW, Huang X, Song BL, Wang Y, Wang YG . Regulation of glucose and lipid metabolism in health and disease
Sci China Life Sci, 2019,62(11):1420-1458.
DOI:10.1007/s11427-019-1563-3URLPMID:31686320 [本文引用: 3]
Glucose and fatty acids are the major sources of energy for human body. Cholesterol, the most abundant sterol in mammals, is a key component of cell membranes although it does not generate ATP. The metabolisms of glucose, fatty acids and cholesterol are often intertwined and regulated. For example, glucose can be converted to fatty acids and cholesterol through de novo lipid biosynthesis pathways. Excessive lipids are secreted in lipoproteins or stored in lipid droplets. The metabolites of glucose and lipids are dynamically transported intercellularly and intracellularly, and then converted to other molecules in specific compartments. The disorders of glucose and lipid metabolism result in severe diseases including cardiovascular disease, diabetes and fatty liver. This review summarizes the major metabolic aspects of glucose and lipid, and their regulations in the context of physiology and diseases.

[2] Luo J, Yang HY, Song BL . Mechanisms and regulation of cholesterol homeostasis
Nat Rev Mol Cell Biol, 2020,21(4):225-245.
DOI:10.1038/s41580-019-0190-7URLPMID:31848472 [本文引用: 1]
Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.

[3] Lu XY, Shi XJ, Hu A, Wang JQ, Ding Y, Jiang W, Sun M, Zhao XL, Luo J, Qi W, Song BL . Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis
Nature, 2020, doi: http://www.chinagene.cn/article/2020/0253-9772/10.1038/s41586-020-2928-y.
URLPMID:33208969 [本文引用: 1]

[4] Song BL, Sever N, DeBose-Boyd RA. Gp78, a membrane- anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase
Mol Cell, 2005,19(6):829-840.
URLPMID:16168377 [本文引用: 1]

[5] Altmann SW, Davis Jr HR, Zhu LL, Yao XR, Hoos LM, Tetzloff G, Iyer SPN, Maguire M, Golovko A, Zeng M, Wang LQ, Murgolo N, Graziano MP . Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption
Science, 2004,303(5661):1201-1204.
URLPMID:14976318 [本文引用: 1]

[6] Zhang YY, Fu ZY, Wei J, Qi W, Baituola G, Luo J, Meng YJ, Guo SY, Yin HY, Jiang SY, Li YF, Miao HH, Liu Y, Wang Y, Li BL, Ma YT, Song BL . A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption
Science, 2018,360(6393):1087-1092.
URLPMID:29880681 [本文引用: 1]

[7] Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH . Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein
Science, 2001,292(5520):1394-1398.
DOI:10.1126/science.1060458URLPMID:11326085 [本文引用: 1]
Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to an approximately 1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.

[8] Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C . Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Nat Genet, 2003,34(2):154-156.
URLPMID:12730697

[9] Brown MS, Goldstein JL . A receptor-mediated pathway for cholesterol homeostasis
Science, 1986,232(4746):34-47.
URLPMID:3513311 [本文引用: 1]

[10] Yu HJ, Rimbert A, Palmer AE, Toyohara T, Xia YL, Xia F, Ferreira LMR, Chen ZF, Chen T, Loaiza N, Horwitz NB, Kacergis MC, Zhao LP, Consortium B, Soukas AA, Kuivenhoven JA, Kathiresan S, Cowan CA. GPR146 deficiency protects against hypercholesterolemia and atherosclerosis
Cell, 2019, 179(6): 1276-1288.e1214.
[本文引用: 1]

[11] Han FF, Liu X, Chen CF, Liu YN, Du MK, Zhou Y, Liu Y, Song BL, He HH, Wang Y . Hypercholesterolemia risk-associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice
Cell Res, 2020,30(4):363-365.
URLPMID:32203133 [本文引用: 1]

[12] Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH . Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters
Science, 2000,290(5497):1771-1775.
URLPMID:11099417 [本文引用: 1]

[13] Ge L, Wang J, Qi W, Miao HH, Cao J, Qu YX, Li BL, Song BL . The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1
Cell Metab, 2008,7(6):508-519.
URLPMID:18522832 [本文引用: 1]

[14] Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, Shahawy ME, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJP . Efficacy and safety of alirocumab in reducing lipids and cardiovascular events
N Engl J Med, 2015,372(16):1489-1499.
[本文引用: 1]

[15] Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA . Efficacy and safety of evolocumab in reducing lipids and cardiovascular events
N Engl J Med, 2015,372(16):1500-1509.
[本文引用: 1]

[16] Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study(4S). in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S)
Lancet, 1994,344(8934):1383-1389.
[本文引用: 1]