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, Liqing Yu

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

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 ∼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 ∼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.

Original languageEnglish (US)
Pages (from-to)3306-3315
Number of pages10
JournalJournal of lipid research
Volume51
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Keywords

  • Fatty acid oxidation
  • Fatty liver
  • Insulin resistance
  • Lipoprotein secretion
  • Triglyceride hydrolysis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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