HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 31, 22678-22688, August 3, 2007

This Article Full Text Full Text (PDF) Suppplemental Data All Versions of this Article: 282/31/22678    most recent M704213200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choi, C. S. Articles by Shulman, G. I. Search for Related Content PubMed PubMed Citation Articles by Choi, C. S. Articles by Shulman, G. I. Social Bookmarking                      What's this?

Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance^*

Cheol Soo Choi¹, David B. Savage¹², Ameya Kulkarni¹, Xing Xian Yu³, Zhen-Xiang Liu, Katsutaro Morino, Sheene Kim, Alberto Distefano, Varman T. Samuel, Susanne Neschen, Dongyan Zhang, Amy Wang, Xian-Man Zhang, Mario Kahn, Gary W. Cline, Sanjay K. Pandey, John G. Geisler, Sanjay Bhanot³, Brett P. Monia³, and Gerald I. Shulman, Investigator of the Howard Hughes Medical Institute^¶||4

From the Departments of Internal Medicine and ^¶Cellular and Molecular Physiology, ^||Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510 and Isis Pharmaceuticals, Carlsbad, California 92008

Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGAT1 and DGAT2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because we have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase C activation, we next sought to understand the paradoxical reduction in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were associated with reduced expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic genes (CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase C activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation.

Received for publication, May 22, 2007

^* This work was supported in part by United States Public Health Service Grants R01 DK-40936 (to G. I. S.) and P30 DK-45735 (to G. I. S.) and a Distinguished Clinical Scientist Award from the American Diabetes Association. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ These authors contributed equally to this work.

² Supported by the Wellcome Trust.

³ Employee of and owns stock and/or holds stock options in Isis Pharmaceuticals.

⁴ To whom correspondence should be addressed: TAC S269 P. O. Box 9812, Yale University School of Medicine, New Haven, CT 06536-9812. Tel.: 203-785-5447; Fax: 203-737-4059; E-mail: gerald.shulman{at}yale.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Shi and D. Cheng Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E10 - E18. [Abstract] [Full Text] [PDF]

				G. M. Deevska, K. A. Rozenova, N. V. Giltiay, M. A. Chambers, J. White, B. B. Boyanovsky, J. Wei, A. Daugherty, E. J. Smart, M. B. Reid, et al. Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice J. Biol. Chem., March 27, 2009; 284(13): 8359 - 8368. [Abstract] [Full Text] [PDF]

				A. Kotronen, T. Seppanen-Laakso, J. Westerbacka, T. Kiviluoto, J. Arola, A.-L. Ruskeepaa, M. Oresic, and H. Yki-Jarvinen Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver Diabetes, January 1, 2009; 58(1): 203 - 208. [Abstract] [Full Text] [PDF]

				N. Stefan, K. Kantartzis, and H.-U. Haring Causes and Metabolic Consequences of Fatty Liver Endocr. Rev., December 1, 2008; 29(7): 939 - 960. [Abstract] [Full Text] [PDF]

				J. A. Villena, C. S. Choi, Y. Wang, S. Kim, Y.-J. Hwang, Y.-B. Kim, G. Cline, G. I. Shulman, and H. S. Sul Resistance to High-Fat Diet-Induced Obesity but Exacerbated Insulin Resistance in Mice Overexpressing Preadipocyte Factor-1 (Pref-1): A New Model of Partial Lipodystrophy Diabetes, December 1, 2008; 57(12): 3258 - 3266. [Abstract] [Full Text] [PDF]

				C.-L. E. Yen, S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese Jr. Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis J. Lipid Res., November 1, 2008; 49(11): 2283 - 2301. [Abstract] [Full Text] [PDF]

				J. M. Brown, S. Chung, J. K. Sawyer, C. Degirolamo, H. M. Alger, T. Nguyen, X. Zhu, M.-N. Duong, A. L. Wibley, R. Shah, et al. Inhibition of Stearoyl-Coenzyme A Desaturase 1 Dissociates Insulin Resistance and Obesity From Atherosclerosis Circulation, September 30, 2008; 118(14): 1467 - 1475. [Abstract] [Full Text] [PDF]

				N. Anderson and J. Borlak Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis Pharmacol. Rev., September 1, 2008; 60(3): 311 - 357. [Abstract] [Full Text] [PDF]

				A. G. Gomez-Valades, A. Mendez-Lucas, A. Vidal-Alabro, F. X. Blasco, M. Chillon, R. Bartrons, J. Bermudez, and J. C. Perales Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice Diabetes, August 1, 2008; 57(8): 2199 - 2210. [Abstract] [Full Text] [PDF]

				N. S. Singhal, R. T. Patel, Y. Qi, Y.-S. Lee, and R. S. Ahima Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E331 - E338. [Abstract] [Full Text] [PDF]

				X. X. Yu, S. F. Murray, L. Watts, S. L. Booten, J. Tokorcheck, B. P. Monia, and S. Bhanot Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E436 - E445. [Abstract] [Full Text] [PDF]

				M. Adiels, S.-O. Olofsson, M.-R. Taskinen, and J. Boren Overproduction of Very Low-Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1225 - 1236. [Abstract] [Full Text] [PDF]

				C. Minahk, K.-W. Kim, R. Nelson, B. Trigatti, R. Lehner, and D. E. Vance Conversion of Low Density Lipoprotein-associated Phosphatidylcholine to Triacylglycerol by Primary Hepatocytes J. Biol. Chem., March 7, 2008; 283(10): 6449 - 6458. [Abstract] [Full Text] [PDF]

				X. X. Yu, S. K. Pandey, S. L. Booten, S. F. Murray, B. P. Monia, and S. Bhanot Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression Am J Physiol Endocrinol Metab, March 1, 2008; 294(3): E530 - E539. [Abstract] [Full Text] [PDF]

				K. J. Strissel, Z. Stancheva, H. Miyoshi, J. W. Perfield II, J. DeFuria, Z. Jick, A. S. Greenberg, and M. S. Obin Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications Diabetes, December 1, 2007; 56(12): 2910 - 2918. [Abstract] [Full Text] [PDF]