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更新时间:2022-12-08

12.7

鐭ヨ瘑鍒嗗瓙

The Intellectual

鈥滄櫤璇嗗墠娌垮鑰呪€濄€佹繁鍦虫咕瀹為獙瀹よ祫娣辩爺绌跺憳鐜嬬珛閾?/p>

缂栬€呮寜

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鎾版枃 | 鐜嬬珛閾?/strong>

鈼徛?聽 聽 聽 聽 聽 聽 聽銆€鈼徛?聽 聽 聽 聽 聽 聽 聽銆€鈼?/strong>

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鐩墠鍏ㄤ笘鐣屾湁瓒呰繃2浜夸汉闇€瑕佹棩甯告湇鐢ㄤ粬姹€绛夐檷琛€鑴傝嵂鐗╂潵鎺у埗琛€鑴傦紝鍦ㄥ彂杈惧浗瀹剁殑涓€佸勾浜虹兢浣撲腑浣跨敤闄嶈剛鑽墿鐨勬瘮渚嬫洿楂橈紙浠ョ編鍥戒负渚嬶紝45宀佷互涓婁汉缇ゆ湁25%闇€瑕佹棩甯镐娇鐢ㄩ檷鑴傝嵂鐗┞燵1]锛夈€傚彲鎯宠€岀煡锛屼即闅忕潃鍏ㄧ悆鐨勭粡娴庣ぞ浼氬彂灞曞拰鑰侀緞鍖栵紝鍑虹幇琛€鑴傚紓甯搞€侀渶瑕佸尰鐤楀共棰勭殑浜虹兢鍙細瓒婃潵瓒婂銆?/p>

楂樿鑴傘€佺壒鍒槸楂樿儐鍥洪唶锛屽苟涓嶄粎浠呮槸涓畝鍗曠殑楗涔犳儻闂銆備互鑳嗗浐閱囦负渚嬶紝浜轰綋涓殑鑳嗗浐閱囧彧鏈夊ぇ绾?0%鏉ヨ嚜椋熺墿鎽勫叆锛堟瘮濡傝泲榛勫氨鏄瘜鍚儐鍥洪唶鐨勯鐗╋級锛屽叾浣?0%鍒欐潵鑷倽鑴忚嚜韬殑鍚堟垚[2]銆傝繖鏄洜涓鸿儐鍥洪唶鏈韩鏄浜轰綋鏋佸叾閲嶈鐨勭敓鐗╁垎瀛愶紝姣忎竴涓汉浣撶粏鑳炵殑缁嗚優鑶滈兘闇€瑕佺浉褰撴瘮渚嬬殑鑳嗗浐閱囧垎瀛愶紝浠ュ鍔犲叾闊ф€у拰娴佸姩鎬э紱涔熸湁澶ч噺鍥洪唶绫荤殑婵€绱犳槸鐢ㄨ儐鍥洪唶鍒堕€犵殑锛屼緥濡傝偩涓婅吅鐨川婵€绱犮€佸悇绉嶆€ф縺绱犵瓑銆傚洜姝わ紝瀵逛簬鍑虹幇楂樿鑴傞棶棰樼殑浜烘潵璇达紝闄や簡闇€瑕佹敞鎰忛ギ椋熶腑鐨勮儐鍥洪唶鍚噺锛屽線寰€涔熼渶瑕佽嵂鐗╁奖鍝嶄綋鍐呯殑鑳嗗浐閱囦唬璋紙渚嬪闄嶄綆鍏跺悎鎴愬拰鍚告敹锛屼績杩涘叾鍒嗚В鍜屾帓鍑猴級锛屾墠鑳借捣鍒板ソ鐨勯檷鑴傛晥鏋溿€?/p>

闄嶈剛鑽殑閫昏緫

鐩墠鍖昏嵂甯傚満涓婁富瑕佷娇鐢ㄧ殑闄嶈剛鑽墿涔熷ぇ浣撳彲浠ユ寜杩欎釜閫昏緫杩涜鍖哄垎銆?/p>

棣栧綋鍏跺啿鐨勫氨鏄粬姹€绫昏嵂鐗╋紝杩欐槸杩囧幓鍥涘崄骞存椂闂撮噷浣跨敤鏈€涓哄箍娉涚殑闄嶈剛鑽墿銆備粬姹€绫昏嵂鐗╀富瑕侀€氳繃鎶戝埗鑳嗗浐閱囧悎鎴愰€斿緞涓婄殑鍏抽敭閰垛€斺€擧MG-CoA杩樺師閰舵潵璧锋晥銆傝繖绫昏嵂鐗╀腑璇炵敓杩囨浘缁忕殑鈥滆嵂鐜嬧€濓細1992骞翠笂甯傘€佸巻鍙查攢鍞瓒呰繃1000浜跨編鍏冪殑绔嬫櫘濡ャ€?/p>

闄嶈剛鑽鍩熷彟涓€涓柊鍏撮澏鐐规槸PCSK9銆傝嚜2015骞磋捣锛屽凡缁忔湁閽堝PCSK9铔嬬櫧鐨勪袱涓崟鍏嬮殕鎶椾綋鑽墿锛圗volocumab鍜孉lirocumab锛夊拰涓€涓皬鏍搁吀鑽墿(Inclisiran)涓婂競閿€鍞紝瀹冧滑鐨勪綔鐢ㄦ満鍒舵槸淇冭繘鑲濊剰浠庤娑蹭腑鍥炴敹澶氫綑鐨勮儐鍥洪唶銆?/p>

闄や笂杩颁袱澶х被鑽墿涔嬪锛屼緷鎶橀害甯冪瓑闃绘椋熺墿涓殑鑳嗗浐閱囪鑲犻亾鍚告敹鐨勮嵂鐗┿€佽儐姹侀吀铻悎鍓傜瓑淇冭繘鑲濊剰鍒╃敤鑳嗗浐閱囧埗閫犺儐閰搞€佷粠鑰岄檷浣庤儐鍥洪唶鍚噺鐨勮嵂鐗╋紝涔熼兘鏈夊悇鑷殑鐢ㄦ涔嬪湴[3]銆?/p>

鑰孉SGR1杩欎釜闄嶈鑴傜殑鏂伴澏鐐癸紝鍏朵綔鐢ㄦ満鐞嗕笌涓婅堪鐨勯檷琛€鑴傝嵂鐗╁畬鍏ㄤ笉鍚岋紝瀹冩槸閫氳繃淇冭繘鑳嗗浐閱囩殑鎺掓硠鏉ヨ捣鍒伴檷琛€鑴傛晥鏋滅殑銆?/strong>

涓轰簡鏇村ソ鍦拌鏄嶢SGR1鐨勪綔鐢紝鎴戜滑鍏堢矖鐣ユ弿杩颁竴涓嬩汉浣撳唴鑳嗗浐閱囩殑浠h阿璺緞銆?/p>

鑲濊剰鏄儐鍥洪唶浠h阿鐨勬牳蹇冨櫒瀹橈紝鑲濊剰鑷韩鍒堕€犵殑鎴栬€呴鐗╂潵婧愮殑鑳嗗浐閱囧垎瀛愶紝浼氬拰鐢樻补涓夐叝涓€璧峰湪鑲濊剰缁嗚優涓鐗瑰畾鐨勮泲鐧借川鍒嗗瓙鍖呰9锛屽舰鎴愮洿寰勫嚑鍗佺撼绫崇殑寰矑锛岄€氳繃琛€娑茶繍杈撹繘鍏ュ叏韬悇涓櫒瀹橈紝灏嗚儐鍥洪唶鍜岀敇娌逛笁閰緵缁欐墍鏈夌粏鑳炰娇鐢紝杩欏氨鏄墍璋撶殑鈥滃潖鑳嗗浐閱団€?浣庡瘑搴﹁剛铔嬬櫧銆傝€屽叏韬繃鍓╃殑鑳嗗浐閱囷紝鍒欓€氳繃绫讳技鐨勫寘瑁瑰拰閫掗€佹柟寮忛€氳繃琛€娑擦洖鏀跺埌鑲濊剰涓紝杩欏氨鏄墍璋撶殑鈥滃ソ鑳嗗浐閱団€?楂樺瘑搴﹁剛铔嬬櫧銆傝€岃倽鑴忎腑杩囧墿鐨勮儐鍥洪唶涔熸湁鍑犱釜鍘诲锛屽畠浠涔堣鐢ㄤ簬鍒堕€犲浐閱囩被婵€绱犳垨鑰呰儐姹佺殑涓昏鎴愬垎涔嬩竴鈥斺€旇儐閰革紝瑕佷箞鍒欎細琚垎娉屽埌鑳嗗泭涓紝骞朵即闅忚儐姹佽繘鍏ユ秷鍖栫郴缁熻鎺掓硠鍑轰汉浣撱€傝€屽鏋滀笂杩颁富瑕佷唬璋㈢幆鑺傚け琛★紝鑲濊剰涓埗閫犲拰杈撳嚭鐨勮儐鍥洪唶瓒呰繃浜嗕汉浣撻渶瑕侊紝鍒欏氨浼氬嚭鐜伴珮琛€鑴傘€佽剛鑲倽绛夌棁鐘躲€傦紙褰撶劧锛岃繖閲岄渶瑕佸啀娆″己璋冿紝杩欎粎浠呮槸瀵硅儐鍥洪唶浠h阿涓€涓瀬绔矖绯欏拰杩囧害绠€鍖栫殑闃愯堪銆傦級

鍥犳锛屽鏋滆兘澶熶績杩涜儐鍥洪唶閫氳繃鑳嗘眮澶栨帓锛屼篃搴旇鑳藉璧峰埌涓嶉敊鐨勯檷琛€鑴傛晥鏋溿€傝繖涓不鐤楅珮琛€鑴傜殑鏂瑰紡锛屾湁鐐圭被浼间簬鍒楀噣绫昏嵂鐗╃殑闄嶈绯栨晥鏋溿€傝繖绫昏嵂鐗╃殑浣滅敤鏈哄埗鏄姂鍒惰偩鑴忎腑涓€涓悕涓洪挔-钁¤悇绯栧崗鍚岃浆杩愯泲鐧?鐨勮泲鐧借川锛岄樆姝㈣偩鑴忎粠琛€娑蹭腑鍥炴敹钁¤悇绯栧垎瀛愶紝浠庤€岃澶ч噺钁¤悇绯栧垎瀛愰殢灏挎恫鎺掑嚭浣撳銆傝繖涓綔鐢ㄦ満鍒跺苟涓嶆秹鍙婁汉浣撲腑澶嶆潅鐨勮憽钀勭硸浠h阿璺緞锛屽嵈鑳界珛绔胯褰卞湴闄嶄綆琛€绯栨按骞筹紝娌荤枟2鍨嬬硸灏跨梾锛屼篃鑳藉緢濂藉湴棰勯槻绯栧翱鐥呭紩璧风殑蹇冭绠″苟鍙戠棁銆傚洜姝わ紝杩欑被鑽墿鐩墠鍦ㄥ悇鍥界殑绯栧翱鐥呮不鐤楁寚鍗椾腑鍦颁綅鎸佺画涓婂崌[4]銆?/p>

ASGR1鐨勯檷鑴傛満鐞?/strong>

鎴戜滑璇村洖ASGR1杩欎釜闈剁偣銆侫SGR1鐨勫叏绉版槸Asialoglycoprotein Receptor 1锛屽嵆鑴卞斁娑查吀绯栬泲鐧藉彈浣?銆傞【鍚嶆€濅箟锛岃繖鏄粏鑳炶〃闈㈢殑涓€绫诲彈浣撳垎瀛愶紝涓撻棬缁撳悎鍜屾劅鐭ヤ竴绫荤壒娈婄殑绯栧熀鍖栦慨楗扮殑铔嬬櫧璐ㄣ€侫SGR1鍙湪鑲濊剰缁嗚優涓〃杈撅紝鍏跺叿浣撶殑浣滅敤鏈哄埗闀挎湡鏈煡銆備絾宸茬粡鏈変笉灏戦澏鍚戣倽缁嗚優鐨勮嵂鐗╁湪閫氳繃ASGR1鍙椾綋杩涜鍚告敹锛屼緥濡侫lnylam鍏徃寮€鍙戠殑灏忔牳閰歌嵂鐗╋紝灏辨槸閫氳繃娣诲姞鐗规畩鐨勭硸鍩哄寲鍒嗗瓙锛屼粠鑰屼娇鍏惰兘澶熻鑲濊剰缁嗚優琛ㄩ潰鐨凙SGR鎵€璇嗗埆锛屾彁楂樺叾琚倽缁嗚優鍚告敹鐨勮兘鍔沎5]銆?/p>

鍦?016骞达紝涓€椤瑰湪鍐板矝銆佷腹楹﹀拰鑽峰叞浜虹兢涓繘琛岀殑鐮旂┒棣栨鍙戠幇锛孉SGR1鍩哄洜鐨勬煇浜涚綍瑙佸ぉ鐒跺彉寮傦紝鑳藉闄嶄綆鍏跺熀鍥犳椿鎬э紝鍚屾椂鑳藉鏄捐憲闄嶄綆浜虹兢鐨勮鑴傛按骞筹紙鐗瑰埆鏄綆瀵嗗害鑴傝泲鐧斤級鍜屽績琛€绠$柧鐥呴闄┿€傝€屼笖鎼哄甫杩欎簺鍩哄洜缂洪櫡鐨勪汉骞舵病鏈夊嚭鐜颁换浣曞叾浠栨柟闈㈢殑鍋ュ悍闂銆傝繖鏄汉浠涓€娆℃剰璇嗗埌ASGR1鍙兘鎴愪负鍏ㄦ柊鐨勯檷鑴傝嵂鐗╁紑鍙戦澏鐐筟6]銆?/p>

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绗竴涓夊叡锛圖aiichi Sankyo锛?/p>

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[1] Penn Medicine. (2018, Aug 02).聽Statins: What You Should Know.

https://www.pennmedicine.org/updates/blogs/heart-and-vascular-blog/2018/april/statins-what-you-should-know

[2] Harvard Health Publishing. (2017, Feb 06).聽How it鈥檚 made: Cholesterol production in your body.

https://www.health.harvard.edu/heart-health/how-its-made-cholesterol-production-in-your-body

[3] Luo, J., Yang, H., & Song, B.-L. (2020). Mechanisms and regulation of聽cholesterol homeostasis.聽Nature Reviews. Molecular Cell Biology,聽21(4), 225鈥?45.

[4] Lopaschuk, G. D., & Verma, S. (2020). Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors.聽JACC. Basic to Translational Science,聽5(6), 632鈥?44.

[5] Debacker, A. J., Voutila, J., Catley, M., Blakey, D., & Habib, N. (2020). Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug.聽Molecular Therapy,聽28(8), 1759鈥?771.

[6] Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A. B., Norddahl, G. L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., Jonsdottir, I., Steinthorsdottir, V., Rafnar, T., Swinkels, D. W., Galesloot, T. E., Grarup, N., J酶rgensen, T., Vestergaard, H., Hansen, T., 鈥?Krarup, N. T. (2016). Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.聽The New England Journal of Medicine,聽374(22), 2131鈥?141.

[7] Wang, J.-Q., Li, L.-L., Hu, A., Deng, G., Wei, J., Li, Y.-F., Liu, Y.-B., Lu, X.-Y., Qiu, Z.-P., Shi, X.-J., Zhao, X., Luo, J., & Song, B.-L. (2022). Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion.聽Nature (London),聽608(7922), 413鈥?20.

[8] Endo A. (2010). A historical perspective on the discovery of statins.聽Proceedings of the Japan Academy. Series B, Physical and biological sciences,聽86(5), 484鈥?93.

[9] Nair, P. (2013). Brown and Goldstein: The Cholesterol Chronicles.聽Proceedings of the National Academy of Sciences - PNAS,聽110(37), 14829鈥?4832.

[10] Yamamoto, T., Davis, C. G., Brown, M. S., Schneider, W. J., Casey, M. L., Goldstein, J. L., & Russell, D. W. (1984). The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.聽Cell,聽39(1), 27鈥?8.

[11] Brown, M. S., Faust, J. R., Goldstein, J. L., Kaneko, I., & Endo, A. (1978). Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase.聽The Journal of biological chemistry,聽253(4), 1121鈥?128.

[12] Abifadel, M., Varret, M., Rab猫s, J. P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derr茅, A., Vill茅ger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, J. M., Luc, G., Moulin, P., 鈥?Boileau, C. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.聽Nature genetics,聽34(2), 154鈥?56.

[13] Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H. (2005). Low LDL cholesterol in inpiduals of African descent resulting from frequent nonsense mutations in PCSK9.聽Nature genetics,聽37(2), 161鈥?65.

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关键词:涓,€,,叏鏂,伴澏,鐐癸,細浼,氭垚,涓烘,12.7,
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