Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice.
Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice.
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DOI：
10.1016/j.molmet.2016.08.004
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发表时间：
2016-11
影响因子：
8.1
通讯作者：
Spranger J
中科院分区：
文献类型：
--
作者：
Brachs S;Winkel AF;Tang H;Birkenfeld AL;Brunner B;Jahn-Hofmann K;Margerie D;Ruetten H;Schmoll D;Spranger J
非酒精性脂肪肝是一个全球性的健康问题和心脏代谢疾病的危险因素。柠檬酸盐摄取改变细胞内肝脏能量代谢，并由保守的二羧酸钠协同转运蛋白溶质载体家族13成员5（SLC 13 A5，INDY的哺乳动物同系物：mINDY）控制。在果蝇和秀丽隐杆线虫中，INDY的减少降低了全身脂质的积累。Slc 13 a5基因缺失可保护小鼠免受饮食诱导的肥胖和胰岛素抵抗我们假设，诱导性肝脏mINDY抑制应防止脂肪肝和肝脏胰岛素抵抗的发展。成年C57 BL/6 J小鼠随意喂食西方饮食（60%千卡来自脂肪，21%千卡来自碳水化合物）。通过每周注射化学修饰的肝选择性siRNA诱导mINDY的敲低，持续8周。对小鼠进行代谢表征，并使用ipGTT和高胰岛素-正常血糖钳夹评估mINDY抑制对葡萄糖耐量以及胰岛素敏感性的影响。通过生化测量和组织化学测定肝脏脂质蓄积。在8周的干预内，肝脏选择性siRNA抑制肝脏mINDY表达超过60%。在高胰岛素-正常血糖钳夹中，mINDY敲低改善了C57 BL/6 J小鼠的肝胰岛素敏感性（即胰岛素诱导的内源性葡萄糖产生抑制）。此外，siRNA介导的mINDY抑制作用可以防止肝脏中中性脂质储存和甘油三酯积累，而我们发现对体重没有影响。我们发现，诱导型mINDY抑制改善了肝脏胰岛素敏感性，并预防了成年C57 BL 6/J小鼠的饮食诱导的非酒精性脂肪肝疾病。这些作用不依赖于体重或身体成分的变化。在小鼠中通过肝选择性siRNA诱导mINDY/Slc 13 a5敲低。肝脏选择性敲低mINDY可改善肝脏胰岛素敏感性。肝脏选择性敲低mINDY可预防脂肪肝。
Non-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogaster and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance. Adult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. Within the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight. We show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition. mINDY/Slc13a5 knockdown was induced by liver-selective siRNA in mice. Liver-selective knockdown of mINDY improved hepatic insulin sensitivity. Liver-selective knockdown of mINDY prevented steatosis hepatis.
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在四种常用的近交小鼠菌株中的体内葡萄糖代谢。
影响因子：
7.7
作者：
Berglund, Eric D.;Li, Candice Y.;Poffenberger, Greg;Ayala, Julio E.;Fueger, Patrick T.;Willis, Shannon E.;Jewell, Marybeth M.;Powers, Alvin C.;Wasserman, David H.
通讯作者：
Wasserman, David H.
DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
DOI：
10.1152/ajpgi.00371.2006
发表时间：
2007-01-01
影响因子：
4.5
作者：
Gopal, Elangovan;Miyauchi, Seiji;Ganapathy, Vadivel
通讯作者：
Ganapathy, Vadivel
影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
4.1
作者：
Inoue, K;Fei, YJ;Ganapathy, V
通讯作者：
Ganapathy, V