October 2010

[JLR] Better Livers through CGI

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CGI-58 inhibition results in hepatic steatosis in both chow-fed and high fat diet-fed mice.

Mutations in CGI-58 (comparative gene identification-58, also known as Abhd5) lead to Chanarin-Dorfman syndrome, characterized by abnormal accumulation of triglycerides, nonalcoholic fatty liver disease and dry, scaly skin. It’s still unclear how CGI-58 functions to prevent CDS, and CGI-58 knockout mice are neonatal lethal, which hinders integrated lipid and energy metabolism studies. In this article, the researchers circumvented this limitation by using antisense oligonucleotides to inhibit CGI-58 expression in adult mice by up to 95 percent. In chow-fed mice, ASO-mediated depletion of CGI-58 did not affect weight gain, plasma TG or plasma glucose, though it did raise hepatic TG levels ~4-fold. In contrast, in high fat diet-fed mice, CGI-58 depletion protected against diet-induced obesity, even as the hepatic levels of TG, phosphatidylglycerol, diacylglycerols and ceramides all were elevated; these hepatic lipid alterations were associated with significant decreases in hepatic TG-associated enzyme activity and secretion, and reduced plasma concentrations of ketones, nonesterified fatty acids and insulin. In addition, HFD-fed and ASO-treated mice were more glucose-tolerant and insulin-sensitive. Collectively, this study demonstrates a critical role for CGI-58 in maintaining hepatic TG and glycerophospholipid homeostasis and has unmasked an unexpected link between CGI-58 and HFD-induced obesity and insulin resistance.

CGI-58 Knockdown in Mice Causes Hepatic Steatosis, but Prevents Diet-induced Obesity and Glucose Intolerance

J. Mark Brown, Jenna L. Betters, Caleb Lord, Yinyan Ma, Xianlin Han, Kui Yang, Heather M. Alger, John Melchior, Janet Sawyer, Ramesh Shah, Martha D. Wilson, Xiuli Liu, Mark J. Graham, Richard Lee, Rosanne Crooke, Gerald I. Shulman, Bingzhong Xue, Hang Shi and Liqing Yu

J. Lipid Res., published online Aug. 27, 2010 

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