CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance

被引:129
作者
Brown, J. Mark [1 ]
Betters, Jenna L. [1 ]
Lord, Caleb [1 ]
Ma, Yinyan [1 ]
Han, Xianlin [4 ]
Yang, Kui [4 ]
Alger, Heather M. [2 ]
Melchior, John [1 ]
Sawyer, Janet [1 ]
Shah, Ramesh [1 ]
Wilson, Martha D. [1 ]
Liu, Xiuli [5 ]
Graham, Mark J. [6 ]
Lee, Richard [6 ]
Crooke, Rosanne [6 ]
Shulman, Gerald I. [7 ,8 ]
Xue, Bingzhong [3 ]
Shi, Hang [9 ]
Yu, Liqing [1 ,2 ]
机构
[1] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol Sect Lipid Sci, Winston Salem, NC 27157 USA
[2] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA
[3] Wake Forest Univ, Bowman Gray Sch Med, Dept Endocrinol & Metab, Winston Salem, NC 27157 USA
[4] Washington Univ, Sch Med, Dept Internal Med, Div Bioorgan Chem & Mol Pharmacol, St Louis, MO 63110 USA
[5] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44195 USA
[6] Isis Pharmaceut Inc, Antisense Drug Discovery, Cardiovas Grp, Carlsbad, CA 92008 USA
[7] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Internal Med, New Haven, CT 06510 USA
[8] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA
[9] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA
关键词
fatty liver; insulin resistance; triglyceride hydrolysis; lipoprotein secretion; fatty acid oxidation; LIPID STORAGE DISEASE; ADIPOSE TRIGLYCERIDE LIPASE; CHANARIN-DORFMAN-SYNDROME; GENE IDENTIFICATION-58 CGI-58; ELEMENT-BINDING PROTEIN-1C; FATTY LIVER-DISEASE; INSULIN-RESISTANCE; CYTOPLASMIC TRIACYLGLYCEROLS; CHOLESTERYL ESTERS; SHOTGUN LIPIDOMICS;
D O I
10.1194/jlr.M010256
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3306 / 3315
页数:10
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