生物谷報(bào)道：一個(gè)由Mary-Ellen Harper、Robert Dent和Ruth McPherson博士領(lǐng)導(dǎo)的渥太華研究組聯(lián)合來自美國(guó)加州伯克力的研究人員對(duì)AMPK（腺苷單磷酸活化蛋白激酶）基因進(jìn)行了深入研究,。這種酶控制著我們細(xì)胞中的能量數(shù)量,。在兩個(gè)沒有親緣關(guān)系的家族中的成員細(xì)胞中發(fā)現(xiàn)的這種基因的突變導(dǎo)致肌肉中AMPK活性加倍——模擬了運(yùn)動(dòng)時(shí)的能量狀態(tài)。
該研究組還發(fā)現(xiàn),，這種突變導(dǎo)致一種肌肉脂肪儲(chǔ)存量的減少和肌肉糖原的增加,。這一發(fā)現(xiàn)可能用于II型糖尿病的治療，因?yàn)榧∪庵袃?chǔ)存的高水平的脂肪與胰島素抗性的發(fā)生有關(guān),。
另外,，常用的糖尿病藥物甲福明二甲雙胍是通過增加AMPK活性來起作用的。因此,，這項(xiàng)發(fā)現(xiàn)為制藥研究提供了有價(jià)值的信息,。這項(xiàng)研究的發(fā)現(xiàn)還可能引起運(yùn)動(dòng)生理學(xué)家的極大興趣。
這項(xiàng)研究的結(jié)果發(fā)表在9月19日的在線版的PLoS ONE上,，研究獲得了Heart & Stroke Foundation of Ontario資助,。
此前，來自哥倫比亞大學(xué)醫(yī)學(xué)中心的研究人員確定了一種作為細(xì)胞中心能量表的蛋白質(zhì)的復(fù)雜三維結(jié)構(gòu),。這些結(jié)果信息將有助于研究人員了解這種重要蛋白分子AMP蛋白激酶（AMPK）的多種關(guān)鍵細(xì)節(jié)，從而為研發(fā)出新型的糖尿病以及肥胖癥藥物和方法奠定基礎(chǔ),。這項(xiàng)研究的結(jié)果發(fā)表在《科學(xué)》雜志上,，文章揭示了細(xì)胞最基礎(chǔ)及關(guān)鍵的能量過程,。
AMP蛋白激酶（AMPK），它主要控制細(xì)胞新陳代謝：它會(huì)決定身體中的脂肪是儲(chǔ)存還是燃燒,，這主要取決于細(xì)胞中總能量,。當(dāng)細(xì)胞能量水平較高時(shí)，細(xì)胞中存在高濃度的能量分子ATP（三磷酸腺苷）,，因此AMPK會(huì)促使細(xì)胞進(jìn)行“合成代謝”,，將多余能量作為脂肪儲(chǔ)存下來；當(dāng)ATP水平較低時(shí),，AMPK將關(guān)閉合成代謝,，反而激發(fā)分解代謝，讓脂肪燃燒為能量,。
研究人員表示,，AMPK能作為治療2型糖尿病的一種有效手段。當(dāng)AMPK探測(cè)到細(xì)胞中ATP濃度較低時(shí),，它們會(huì)利用各種機(jī)制使細(xì)胞中的葡萄糖變?yōu)锳TP,。對(duì)于嚙齒類動(dòng)物的實(shí)驗(yàn)已經(jīng)表明，AMPK對(duì)于降低血糖是有效的,。
文章的作者表示,，雖然目前他們還不知道如何單獨(dú)激發(fā)AMPK而不帶來副作用，但是了解蛋白質(zhì)的原子水平結(jié)構(gòu)為研究人員提供了一種強(qiáng)大的治療工具,。
AMP激活的蛋白激酶(AMP-activated protein kinase,AMPK)廣泛存在于真核細(xì)胞中,一旦被激活,即可磷酸化下游靶蛋白,關(guān)閉消耗ATP的合成代謝途徑,開啟產(chǎn)生ATP的分解代謝途徑,被稱為"細(xì)胞能量調(diào)節(jié)器"
在調(diào)節(jié)細(xì)胞能量狀態(tài)的蛋白激酶級(jí)聯(lián)反應(yīng)中,，AMP激活的蛋白激酶(AMPK)是其中樞組成部分。AMPK的活性受AMP/ATP比值的調(diào)節(jié).應(yīng)激反應(yīng)可通過ATP的產(chǎn)生減少或利用增加,，使細(xì)胞內(nèi)AMP/ATP的比值增加,，從而激活A(yù)MPK.激活的AMPK可激發(fā)一系列的反應(yīng)來恢復(fù)細(xì)胞內(nèi)的能量平衡。AMPK可啟動(dòng)分解代謝途徑,，如脂肪酸氧化和糖酵解,，從而增加ATP的產(chǎn)生，同時(shí)關(guān)閉合成代謝途徑,，如脂肪酸合成和蛋白合成,，減少ATP的消耗。AMPK不僅可以在細(xì)胞水平作為能量的感受器,，還可以通過激素和細(xì)胞因子,，如瘦素、脂聯(lián)素和ghrelin來參與調(diào)節(jié)機(jī)體的能量消耗和能量攝入,。
糖原是動(dòng)物體內(nèi)糖的貯存形式,攝入的糖類大部分轉(zhuǎn)變成甘油三酯貯存在脂肪組織中,，只有小部分以糖原形式貯存。其意義在于當(dāng)機(jī)體需要葡萄糖時(shí)它可以迅速被動(dòng)用以供急需。糖原合成與分解的生理性調(diào)節(jié)主要靠胰島素和胰高血糖素,。機(jī)體血糖降低可引起胰高血糖素和腎上腺素分泌增加,，此時(shí)細(xì)胞內(nèi)cAMP含量增加，促使有活性的A激酶增加,。A激酶一方面時(shí)糖原合酶磷酸化失去活性,，一方面通過磷酸化酶b激酶使磷酸化酶變成有活性的磷酸化酶a，最終結(jié)果使糖原合成減少,，糖原分解增加,，使血糖升高。
原始出處:
PLoS ONE
Received: July 16, 2007; Accepted: August 14, 2007; Published: September 19, 2007
Gain-of-Function R225W Mutation in Human AMPKγ3 Causing Increased Glycogen and Decreased Triglyceride in Skeletal Muscle
Sheila R. Costford1#, Nihan Kavaslar2#, Nadav Ahituv4, Shehla N. Chaudhry1, Wendy S. Schackwitz4,5, Robert Dent3, Len A. Pennacchio4, Ruth McPherson2#, Mary-Ellen Harper1*#
1 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, 2 Division of Cardiology and Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada, 3 Ottawa Hospital Weight Management Clinic, Ottawa, Ontario, Canada, 4 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, 5 United States Department of Energy Joint Genome Institute, Walnut Creek, California, United States of America
Abstract
Background
AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory γ3 subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations [1]–[3]. Here we report the first gain-of-function mutation in the muscle-specific regulatory γ3 subunit in humans.
Methods and Findings
We sequenced the exons and splice junctions of the AMPK γ3 gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The γ3 R225W mutation is homologous in location to the γ2R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the γ3R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN-) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a ~90% increase of skeletal muscle glycogen content and a ~30% decrease in intramuscular triglyceride (IMTG).
Conclusions
We have identified for the first time a mutation in the skeletal muscle-specific regulatory γ3 subunit of AMPK in humans. The γ3R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK γ3 in human muscle energy metabolism.
