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J. Biol. Chem., Vol. 280, Issue 22, 21506-21514, June 3, 2005

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Increased Very Low Density Lipoprotein Secretion and Gonadal Fat Mass in Mice Overexpressing Liver DGAT1^*

Tomomi Yamazaki, Eriko Sasaki, Chihaya Kakinuma, Takashi Yano, Shinji Miura, and Osamu Ezaki¶

From the Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan and Mochida Pharmaceutical Company Limited, 722 Jimba-aza-uenohara, Gotemba, Shizuoka 412-8524, Japan

Acyl-CoA:diacylglycerol acyltransferases (DGATs) catalyze the last step in triglyceride (TG) synthesis. The genes for two DGAT enzymes, DGAT1 and DGAT2, have been identified. To examine the roles of liver DGAT1 and DGAT2 in TG synthesis and very low density lipoprotein (VLDL) secretion, liver DGAT1- and DGAT2-overexpressing mice were created by adenovirus-mediated gene transfection. DGAT1-overexpressing mice had markedly increased DGAT activity in the presence of the permeabilizing agent alamethicin. This suggests that DGAT1 possesses latent DGAT activity on the lumen of the endoplasmic reticulum. DGAT1-overexpressing mice showed increased VLDL secretion, resulting in increased gonadal (epididymal or parametrial) fat mass but not subcutaneous fat mass. The VLDL-mediated increase in gonadal fat mass might be due to the 4-fold greater expression of the VLDL receptor protein in gonadal fat than in subcutaneous fat. DGAT2-overexpressing mice had increased liver TG content, but VLDL secretion was not affected. These results indicate that DGAT1 but not DGAT2 has a role in VLDL synthesis and that increased plasma VLDL concentrations may promote obesity, whereas increased DGAT2 activity has a role in steatosis.

Received for publication, November 17, 2004 , and in revised form, March 22, 2005.

^* This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by research grants from the Ministry of Health, Labor, and Welfare of Japan, and by a grant from the Program for the Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-3-3203-5725; Fax: 81-3-3207-3520; E-mail: ezaki{at}nih.go.jp.

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