CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance
CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance
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DOI：
10.1194/jlr.m010256
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发表时间：
2010-11-01
影响因子：
6.5
通讯作者：
Yu, Liqing
中科院分区：
文献类型：
--
作者：
Brown, J. Mark;Betters, Jenna L.;Yu, Liqing
人类比较基因识别-58(CGI-58)的突变导致甘油三酯(TG)在多个组织中积聚。缺乏CGI-58基因的小鼠出生后不久就会因为皮肤屏障缺陷而死亡。为了研究CGI-58在整合的脂质和能量代谢中的作用，我们利用反义寡核苷酸(ASO)抑制成年小鼠CGI-58的表达。用两种不同的CGI-58靶向ASO治疗后，肝脏和白色脂肪组织中CGI-58蛋白表达的下调幅度接近80%-95%。在喂养食物的小鼠中，ASO介导的CGI-58的耗尽并没有改变体重增加、血浆甘油三酯或血糖，但使肝脏甘油三酯水平增加了近4倍。当用高脂饮食(HFD)攻击时，CGI-58ASO处理的小鼠可以防止饮食诱导的肥胖，但它们的肝脏甘油三酯、二酰甘油和神经酰胺的含量都增加了，有趣的是，它们的肝脏磷脂酰甘油含量增加了10倍。这些肝脏脂质改变与肝脏甘油三酯水解酶活性、肝脂蛋白-甘油三酯分泌以及血浆中酮、非酯化脂肪酸和胰岛素浓度的显著降低有关。此外，HFD喂养的CGI-58 ASO处理的小鼠更耐葡萄糖，对胰岛素更敏感。总而言之，这项工作证明了CGI-58在限制肝脏脂肪变性和维持肝脏甘油磷脂稳态方面发挥了关键作用，并揭示了CGI-58在促进由HFD引起的肥胖和胰岛素抵抗方面的意想不到的作用。-Brown，J.M.，J.L.Betters，C.Lord，Y.Ma，X.han，K.Yang，H.M.Alger，J.Melchior，J.Sawyer，R.Shah，M.D.Wilson，X.Liu，M.J.Graham，R.Lee，R.Crooke，G.I.Shulman，B.Sue，H.Shih，和L.Yu.在小鼠中，CGI-58基因敲除会导致肝脏脂肪变性，但可以防止饮食诱导的肥胖和葡萄糖耐量减低。J.Lipid Res.2010年。51：3306-3315。
Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in similar to 80-95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels similar to 4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.-Brown, J. M., J. L. Betters, C. Lord, Y. Ma, X. Han, K. Yang, H. M. Alger, J. Melchior, J. Sawyer, R. Shah, M. D. Wilson, X. Liu, M. J. Graham, R. Lee, R. Crooke, G. I. Shulman, B. Xue, H. Shi, and L. Yu. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. J. Lipid Res. 2010. 51: 3306-3315.