非酒精性脂肪性肝病（NAFLD）是指除酒精外和其他明確的損肝因素所致的,，以彌漫性肝細(xì)胞大泡性脂肪變?yōu)橹饕卣鞯腎陸床病理綜合征,，包括單純性脂肪肝以及由其演變的脂肪性肝炎（NASH）和肝硬化,。
近日，來自舊金山猶他大學(xué)和加州大學(xué)的科研人員通過動物實(shí)驗(yàn)發(fā)現(xiàn)：斑馬魚體內(nèi)一個(gè)編碼轉(zhuǎn)運(yùn)β-羥基丁酸酮體的基因一旦發(fā)生突變后,，脂肪等脂類會在斑馬魚的肝臟組織中大量聚集,。這項(xiàng)最新研究成果發(fā)表在Genes & Dev雜志上，該研究為科學(xué)家研究人類脂肪性肝病的發(fā)生發(fā)展機(jī)制提供了一個(gè)人新的思路,。
目前,，醫(yī)學(xué)上一直沒有合適的方法降低肝臟組織內(nèi)聚集過多的脂肪物質(zhì)，也沒有科學(xué)的方法用力逆轉(zhuǎn)NAFLD導(dǎo)致的肝臟損害,。這項(xiàng)研究通過研究調(diào)控脂類物質(zhì)在肝臟中聚集的基因,，解釋了NAFLD發(fā)生的生理機(jī)制。”
早期研究證明人體內(nèi)存在許多調(diào)控脂肪物質(zhì)代謝的蛋白質(zhì),，而這些蛋白質(zhì)同樣也表達(dá)于斑馬魚,。該項(xiàng)研究的主要人員--Schlegel博士等科學(xué)家通過研究一種名為紅月亮（rmn）的斑馬魚變異株，發(fā)現(xiàn)此斑馬魚體內(nèi)肝臟組織會發(fā)生異常的脂質(zhì)聚集現(xiàn)象,。當(dāng)將這種斑馬魚控制在空腹?fàn)顟B(tài)時(shí),，斑馬魚體內(nèi)就不會出現(xiàn)肝臟炎癥或者肝臟損害的現(xiàn)象。研究人員運(yùn)用定位克隆分子基因技術(shù)篩選出斑馬魚體內(nèi)基因組中的變異基因,。結(jié)果發(fā)現(xiàn)一種名為slc16a6a的基因處于失活狀態(tài),，而slc16a6a基因恰巧是編碼機(jī)體空腹時(shí)運(yùn)送營養(yǎng)物質(zhì)出肝臟的轉(zhuǎn)運(yùn)蛋白的關(guān)鍵基因。
在這項(xiàng)研究之前,，還沒有一項(xiàng)研究對Slc16a6a的蛋白活性的功能開展過相關(guān)研究,。這篇研究論文提示Slc16a6a是可能一種β-羥基丁酸（一種酮體物質(zhì)）的轉(zhuǎn)運(yùn)蛋白。研究人員表示：當(dāng)rmn變異株在禁食狀態(tài)下時(shí),，Slc16a6a基因處于失活狀態(tài),，致使酮體不能及時(shí)從肝臟轉(zhuǎn)運(yùn)出,，導(dǎo)致脂類物質(zhì)在肝臟組織中大量聚集。而一旦將Slc16a6a蛋白導(dǎo)入rmn斑馬魚變異株肝臟之后,，肝臟會恢復(fù)酮體轉(zhuǎn)運(yùn)功能,。
雖然研究人員還不明確禁食狀態(tài)下代謝狀況的改變是否會影響非酒精性脂肪肝的發(fā)生發(fā)展。但是在禁食狀態(tài)下,，Slc16a6a蛋白對于肝臟細(xì)胞轉(zhuǎn)運(yùn)酮體是必需的,。（生物谷 Bioon.com)
doi:10.1101/gad.180968.111
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A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting
Sarah E. Hugo,Lourdes Cruz-Garcia,Santhosh Karanth,Ryan M. Anderson,Didier Y.R. Stainier and Amnon Schlegel
To find new genes that influence liver lipid mass, we performed a genetic screen for zebrafish mutants with hepatic steatosis, a pathological accumulation of fat. The red moon (rmn) mutant develops hepatic steatosis as maternally deposited yolk is depleted. Conversely, hepatic steatosis is suppressed in rmn mutants by adequate nutrition. Adult rmn mutants show increased liver neutral lipids and induction of hepatic lipid biosynthetic genes when fasted. Positional cloning of the rmn locus reveals a loss-of-function mutation in slc16a6a (solute carrier family 16a, member 6a), a gene that we show encodes a transporter of the major ketone body β-hydroxybutyrate. Restoring wild-type zebrafish slc16a6a expression or introducing human SLC16A6 in rmn mutant livers rescues the mutant phenotype. Radiotracer analysis confirms that loss of Slc16a6a function causes diversion of liver-trapped ketogenic precursors into triacylglycerol. Underscoring the importance of Slc16a6a to normal fasting physiology, previously fed rmn mutants are more sensitive to death by starvation than are wild-type larvae. Our unbiased, forward genetic approach has found a heretofore unrecognized critical step in fasting energy metabolism: hepatic ketone body transport. Since β-hydroxybutyrate is both a major fuel and a signaling molecule in fasting, the discovery of this transporter provides a new direction for modulating circulating levels of ketone bodies in metabolic diseases.
