| CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. | |
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MedLine Citation:
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PMID: 20802159 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-27 |
Journal Detail:
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Title: Journal of lipid research Volume: 51 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-13 Completed Date: 2011-01-19 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 3306-15 Citation Subset: IM |
Affiliation:
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Departments of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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1-Acylglycerol-3-Phosphate O-Acyltransferase
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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, secretion Male Mice Mice, Inbred C57BL Obesity / etiology, genetics, prevention & control* Oligonucleotides, Antisense / genetics Phospholipids / metabolism Triglycerides / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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1F32DK084582-01/DK/NIDDK NIH HHS; 1K99-HL096166-01/HL/NHLBI NIH HHS; 5P01HL049373-17/HL/NHLBI NIH HHS; 5P01HL057278-09/HL/NHLBI NIH HHS; R01DK085176/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Dietary Fats; 0/Oligonucleotides, Antisense; 0/Phospholipids; 0/Triglycerides; EC 2.3.1.51/1-Acylglycerol-3-Phosphate O-Acyltransferase; EC 2.3.1.51/Abhd5 protein, mouse |
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