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Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance
Open accessAbstract
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 epsilon 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 epsilon activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation.
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“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [25]
In the citing paper
“Recent studies have shown that increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of the protein kinase C epsilon isoform, resulting in reduced insulin signaling and hepatic insulin resistance.23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [25]
Citations
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751
Prevalence of Hepatic Steatosis in An Urban Population in the United States: Impact of Ethnicity
Browning, J. D., Szczepaniak, L. S., Dobbins, R., Nuremberg, P., Horton, J. D., Cohen, J. C., Grundy, S. M., & Hobbs, H. H. (2004) · Hepatology · doi:10.1002/hep.20466 · Cited by 3,664
Mechanism of activation of protein kinase B by insulin and IGF‐1.
Alessi, D. R., Andjelković, M., Caudwell, B., Cron, P. D., MORRICE, N. A., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,014
Cellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714
Self-citationMolecular mediators of hepatic steatosis and liver injury
Browning, J. D., & Horton, J. D. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422422 · Cited by 1,772
Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561
Self-citationMechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322
Self-citationCases, S., Smith, S. J., Zheng, Y.-W., Myers, H. M., Lear, S. R., Sande, E., Novak, S., Collins, C. C., Welch, C. L., Lusis, A. J., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.22.13018 · Cited by 1,138
Enzymes of triacylglycerol synthesis and their regulation
Coleman, R. (2003) · Progress in Lipid Research · doi:10.1016/s0163-7827(03)00051-1 · Cited by 985
Petersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005) · Diabetes · doi:10.2337/diabetes.54.3.603 · Cited by 911
Self-citationObesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat
Smith, S. J., Cases, S., Jensen, D. R., Chen, H. C., Sande, E., Tow, B., Sanan, D. A., Raber, J., Eckel, R. H., & Farese, R. V. (2000) · Nature Genetics · doi:10.1038/75651 · Cited by 895
Etiology of Insulin Resistance
Petersen, K. F., & Shulman, G. I. (2006) · The American Journal of Medicine · doi:10.1016/j.amjmed.2006.01.009 · Cited by 825
Self-citationCloning of DGAT2, a Second Mammalian Diacylglycerol Acyltransferase, and Related Family Members
Cases, S., Stone, S. J., Zhou, P., Yen, E., Tow, B., Lardizabal, K. D., Voelker, T., & Farese, R. V. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106219200 · Cited by 818
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121164498 · Cited by 753
Self-citationLipopenia and Skin Barrier Abnormalities in DGAT2-deficient Mice
Stone, S. J., Myers, H. M., Watkins, S. M., Brown, B. E., Feingold, K. R., Elias, P. M., & Farese, R. V. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311000200 · Cited by 612
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497
Self-citationFatty Acid Regulation of Hepatic Gene Transcription
Jump, D. Β., Botolin, D., Wang, Y., Xu, J., Christian, B., & Demeure, O. (2005) · Journal of Nutrition · doi:10.1093/jn/135.11.2503 · Cited by 477
Ou, J., Tu, H., Shan, B., Luk, A. Y., DeBose‐Boyd, R. A., Bashmakov, Y. K., Goldstein, J. L., & Brown, M. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111138698 · Cited by 474
An, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., & Newgard, C. B. (2004) · Nature Medicine · doi:10.1038/nm995 · Cited by 450
Self-citationSavage, D. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27300 · Cited by 447
Self-citationMetabolic Significance of Nonalcoholic Fatty Liver Disease in Nonobese, Nondiabetic Adults
Kim, H. J., Kim, H. J., Lee, K. E., Kim, D. J., Kim, S. K., Ahn, C. W., Lim, S., Kim, K. R., Lee, H. C., Huh, K. B., et al. (2004) · Archives of Internal Medicine · doi:10.1001/archinte.164.19.2169 · Cited by 434
Self-citationThe role of AMP‐activated protein kinase in mitochondrial biogenesis
Reznick, R. M., & Shulman, G. I. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.109512 · Cited by 375
Self-citationIncreased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1
Chen, H. C., Smith, S. J., Ladha, Z., Jensen, D. R., Ferreira, L. D., Pulawa, L. K., McGuire, J. G., Pitas, R. E., Eckel, R. H., & Farese, R. V. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14672 · Cited by 335
Dentin, R. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25256 · Cited by 315
Coordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids.
Jump, D. Β., Clarke, S. D., Thelen, A. P., & Liimatta, M. B. (1994) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40103-8 · Cited by 305
Yu, X. X., Murray, S. F., Pandey, S., Booten, S. L., Bao, D., Song, X., Kelly, S., Chen, S., McKay, R. A., Monia, B. P., et al. (2005) · Hepatology · doi:10.1002/hep.20783 · Cited by 305
Self-citationNeschen, S., Morino, K., Hammond, L. E., Zhang, D., Liu, Z.-X., Romanelli, A. J., Cline, G. W., Pongratz, R. L., Zhang, X.-M., Choi, C. S., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.006 · Cited by 261
Self-citationKim, J. K., Gimeno, R. E., Higashimori, T., Kim, H., Choi, H., Punreddy, S., Mozell, R. L., Tan, G., Stricker‐Krongrad, A., Hirsch, D. J., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18917 · Cited by 254
Self-citationFolli, F. B., Saad, M. J. A., Backer, J., & Kahn, C. R. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41650-x · Cited by 251
Rossetti, L., & Giaccari, A. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114636 · Cited by 246
Crooke, R. M., Graham, M. J., Lemonidis, K. M., Whipple, C. P., Koo, S., & Perera, R. J. (2005) · Journal of Lipid Research · doi:10.1194/jlr.m400492-jlr200 · Cited by 227
McKay, R. A., Miraglia, L. J., Cummins, L. L., Owens, S. R., Sasmor, H. M., & Dean, N. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.3.1715 · Cited by 220
Kim, J. K., Gimeno, R. E., Higashimori, T., Kim, H., Choi, H., Punreddy, S., Mozell, R. L., Tan, G., Stricker‐Krongrad, A., Hirsch, D. J., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200418917 · Cited by 212
Self-citationMGAT2, a Monoacylglycerol Acyltransferase Expressed in the Small Intestine
Yen, C. E., & Farese, R. V. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301633200 · Cited by 207
Peroxynitrite increases iNOS through NF-κB and decreases prostacyclin synthase in endothelial cells
Cooke, C. M., & Davidge, S. T. (2002) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00295.2001 · Cited by 180
Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity
Chen, H. C., & Farese, R. V. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000151874.81059.ad · Cited by 169
Seppala-Lindroos, A. (2002) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.7.3023 · Cited by 168
Cao, J., Lockwood, J., Burn, P., & Shi, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300139200 · Cited by 143
Considine, R. V., Nyce, M. R., Allen, L. E., Morales, L. M., Triester, S., Serrano, J., Colberg, J., Lanza-Jacoby, S., & Caro, J. F. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118001 · Cited by 141
Watts, L. M., Manchem, V. P., Leedom, T. A., Rivard, A. L., McKay, R. A., Bao, D., Neroladakis, T., Monia, B. P., Bodenmiller, D. M., Cao, J. X. C., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1846 · Cited by 136
Self-citationMuscle Long‐Chain Acyl CoA Esters and Insulin Resistance
Cooney, G. J., Thompson, A. L., Furler, S. M., Ye, J.-M., & Kraegen, E. W. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04276.x · Cited by 131
Qu, X.-Q., Seale, J., & Donnelly, R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1620207 · Cited by 123
A novel, noninvasive method for the measurement of intestinal fat absorption
Jandacek, R. J., Heubi, J. E., & Tso, P. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.04.007 · Cited by 117
Lehner, R. S., & Kuksis, A. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)52942-2 · Cited by 106
Catalytic properties of MGAT3, a putative triacylgycerol synthase
Cao, J., Cheng, L., & Shi, Y. (2006) · Journal of Lipid Research · doi:10.1194/jlr.m600331-jlr200 · Cited by 96
Chen, H. C., Jensen, D. R., Myers, H. M., Eckel, R. H., & Farese, R. V. (2003) · Journal of Clinical Investigation · doi:10.1172/jci15859 · Cited by 96
Ishigaki, Y., Katagiri, H., Yamada, T., Ogihara, T., Imai, J., Uno, K., Hasegawa, Y., Gao, J., Ishihara, H., Shimosegawa, T., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.2.322 · Cited by 72
Youn, J. H., & Buchanan, T. A. (1993) · Diabetes · doi:10.2337/diab.42.5.757 · Cited by 64
Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance?
Shmueli, E., Alberti, K. G. M. M., & Record, C. O. (1993) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.1993.tb00761.x · Cited by 61
Research works printed but not linked: 5
- Seppala-Lindroos, 2002, J. Clin. Endocrinol. Metab., 87, 3023, 10.1210/jcem.87.7.8638 · DOI · Paper page
- Chen, 2002, J. Clin. Investig., 109, 1049, 10.1172/JCI0214672 · DOI
- Ohshima, 1984, Am. J. Physiol., 246, E193
- Bligh, 1959, Can. J. Biochem. Physiol., 37, 911, 10.1139/y59-099 · DOI · Paper page
- Streeper, 2006, Am. J. Physiol., 291, E388
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Metadata
- Authors
- Choi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., Zhang, D., Wang, A., Zhang, X.-M., Kahn, M., Cline, G. W., Pandey, S. K., Geisler, J. G., Bhanot, S., Monia, B. P., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 31
- Pages
- 22678-22688
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1976094170
- Cited by
- 383
- References
- 51
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 17 · 2023: 19 · 2022: 15 · 2021: 17 · 2020: 22 · 2019: 26 · 2018: 22 · 2017: 21 · 2016: 16 · 2015: 31 · 2014: 26 · 2013: 15 · 2012: 20
- FWCI
- 17.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Wellcome Trust
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK040936, P30DK045735)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- diacylglycerol acyltransferase 2, DGAT1, antisense oligonucleotides, non-alcoholic fatty liver disease, hepatic steatosis, insulin resistance, triglyceride synthesis, diacylglycerol, protein kinase C epsilon, SREBP-1c, lipogenesis, fatty acid oxidation, high-fat diet, type 2 diabetes
- MeSH terms
- Animals, Diet, Fatty Acids, Fatty Liver, Insulin Resistance, Liver, Male, Oxygen, Triglycerides, Oligonucleotides, Antisense, Rats, Sprague-Dawley, Hepatocytes, Diacylglycerol O-Acyltransferase, Rats
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