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

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.

• Authors: 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
• Journal: Journal of lipid research (J Lipid Res) Vol. 51 Issue 11 Pg. 3306-15 (Nov 2010) ISSN: 1539-7262 [Electronic] United States
• PMID: 20802159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Oligonucleotides, Antisense
• Phospholipids
• Triglycerides
• 1-Acylglycerol-3-Phosphate O-Acyltransferase
• Abhd5 protein, mouse

Topics

• 1-Acylglycerol-3-Phosphate O-Acyltransferase (deficiency, genetics)
• Adipocytes, White (metabolism)
• Animals
• Diet (adverse effects)
• Dietary Fats (adverse effects)
• Fatty Liver (genetics, metabolism)
• Gene Expression Regulation (genetics)
• Gene Knockdown Techniques
• Glucose Intolerance (etiology, genetics, prevention & control)
• Insulin Resistance (genetics)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Obesity (etiology, genetics, prevention & control)
• Oligonucleotides, Antisense (genetics)
• Phospholipids (metabolism)
• Triglycerides (metabolism)