期刊
JOURNAL OF LIPID RESEARCH
卷 51, 期 11, 页码 3306-3315出版社
ELSEVIER
DOI: 10.1194/jlr.M010256
关键词
fatty liver; insulin resistance; triglyceride hydrolysis; lipoprotein secretion; fatty acid oxidation
资金
- Wake Forest University Health Sciences
- American Heart Association
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK085176, 1F32DK084582-01]
- National Heart, Lung, and Blood Institute [1K99-HL096166-01, 5P01HL049373-17, 5P01HL057278-09]
- LipoSpectrum LLC
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据