CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance.
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.
Brown
J Mark
JM
Departments of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Betters
Jenna L
JL
Lord
Caleb
C
Ma
Yinyan
Y
Han
Xianlin
X
Yang
Kui
K
Alger
Heather M
HM
Melchior
John
J
Sawyer
Janet
J
Shah
Ramesh
R
Wilson
Martha D
MD
Liu
Xiuli
X
Graham
Mark J
MJ
Lee
Richard
R
Crooke
Rosanne
R
Shulman
Gerald I
GI
Xue
Bingzhong
B
Shi
Hang
H
Yu
Liqing
L
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency* / Q000235:genetics*; D052438:Adipocytes, White / Q000378:metabolism; D000818:Animals; D004032:Diet / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D018149:Glucose Intolerance / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010743:Phospholipids / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D016376:Oligonucleotides, Antisense; D010743:Phospholipids; D014280:Triglycerides; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C492986:Abhd5 protein, mouse
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