Liver Biology and Pathobiology

You have full text access to this OnlineOpen article

Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice†

  1. Xing Xian Yu,
  2. Susan F. Murray,
  3. Sanjay K. Pandey,
  4. Sheri L. Booten,
  5. Dingjiu Bao,
  6. Xiu-Zhen Song,
  7. Susan Kelly,
  8. Songyuan Chen,
  9. Robert McKay,
  10. Brett P. Monia,
  11. Sanjay Bhanot‡,*

Article first published online: 6 JUL 2005

DOI: 10.1002/hep.20783

Issue

Hepatology

Hepatology

Volume 42, Issue 2, pages 362–371, August 2005

Additional Information

How to Cite

Yu, X. X., Murray, S. F., Pandey, S. K., Booten, S. L., Bao, D., Song, X.-Z., Kelly, S., Chen, S., McKay, R., Monia, B. P. and Bhanot, S. (2005), Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology, 42: 362–371. doi: 10.1002/hep.20783

Author Information

  1. Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA

  1. ‡

    fax: 760-603-2600

*Isis Pharmaceuticals, Inc., Department of Antisense Drug Discovery, 2292 Faraday Avenue, Carlsbad, CA 92008

  1. †

    Potential conflict of interest: Nothing to report.

Publication History

  1. Issue published online: 15 JUL 2005
  2. Article first published online: 6 JUL 2005
  3. Manuscript Accepted: 5 MAY 2005
  4. Manuscript Received: 16 DEC 2004

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (617K)

References

  • 1
    Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114: 147–152.
  • 2
    Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 2000; 25: 87–90.
  • 3
    Farese RV Jr, Cases S, Smith SJ. Triglyceride synthesis: insights from the cloning of diacylglycerol acyltransferase. Curr Opin Lipidol 2000; 11: 229–234.
  • 4
    Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, et al. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci U S A 1998; 95: 13018–13023.
  • 5
    Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem 2001; 276: 38870–38876.
  • 6
    Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, Pulawa LK, et al. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 2002; 109: 1049–1055.
  • 7
    Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, et al. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J Biol Chem 2004; 279: 11767–11776.
  • 8
    Dean NM, Butler M, Monia BP, Manoharan M. Pharmacology of 2′-O-(2-methoxy)ethyl-modified antisense oligonucleotide. In: CrookeST, ed. Antisense Drug Technology: Principles, Strategies and Applications. New York, NY: Dekker, 2001: 319–338.
  • 9
    Neufeld DS. Isolation of rat liver hepatocytes. Methods Mol Biol 1997; 75: 145–151.
  • 10
    Yu XX, Drackley JK, Odle J. Rates of mitochondrial and peroxisomal beta-oxidation of palmitate change during postnatal development and food deprivation in liver, kidney and heart of pigs. J Nutr 1997; 127: 1814–1821.
  • 11
    Jiang G, Li Z, Liu F, Ellsworth K, Yang QD, Wu M, et al. Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Invest 2005; 10: 115: 1030–1038.
  • 12
    Desai UJ, Slosberg ED, Boettcher BR, Caplan SL, Fanelli B, Stephan Z, et al. Phenotypic correction of diabetic mice by adenovirus-mediated glucokinase expression. Diabetes 2001; 50: 2287–2295.
  • 13
    Crooke RM, Graham MJ, Lemonidis KM, Whipple C, Koo S, Perera RJ. An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. J Lipid Res 2005; 46: 872–884.
  • 14
    Metzger S, Hassin T, Barash V, Pappo O, Chajek-Sheul T. Reduced body fat and increased hepatic lipid synthesis in mice bearing interleukin-6-secreting tumor. Am J Physiol Endocrinol Metab 2001; 281: E957–E965.
  • 15
    Akiyama T, Tachibana I, Shirohara H, Watanabe N, Otsuki M. High-fat hypercaloric diet induces obesity, glucose intolerance and hyperlipidemia in normal adult male Wistar rat. Diabetes Res Clin Pract 1996; 31: 27–35.
  • 16
    Axen KV, Dikeakos A, Sclafani A. High dietary fat promotes syndrome X in nonobese rats. J Nutr 2003; 133: 2244–2249.
  • 17
    Chen MT, Kaufman LN, Spennetta T, Shrago E. Effects of high fat-feeding to rats on the interrelationship of body weight, plasma insulin, and fatty acyl-coenzyme A esters in liver and skeletal muscle. Metabolism 1992; 41: 564–569.
  • 18
    Murase T, Mizuno T, Omachi T, Onizawa K, Komine Y, Kondo H, et al. Dietary diacylglycerol suppresses high fat and high sucrose diet-induced body fat accumulation in C57BL/6J mice. J Lipid Res 2001; 42: 372–378.
  • 19
    Adeli K, Taghibiglou C, Van Iderstine SC, Lewis GF. Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Trends Cardiovasc Med 2001; 11: 170–176.
  • 20
    Julius U. Influence of plasma free fatty acids on lipoprotein synthesis and diabetic dyslipidemia. Exp Clin Endocrinol Diabetes 2003; 111: 246–250.
  • 21
    Mayes PA. Cholesterol synthesis, transport and excretion. In: MurrayRK, GrannerDK, MayesPA, RodwellVW, eds. Harper's Biochemistry. 23rd ed. Norwalk, CT: Appleton and Lange, 1993: 266–278.
  • 22
    Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K, Sakaue H, et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes 2002; 51: 1672–1680.
  • 23
    Guillet-Deniau I, Mieulet V, Le Lay S, Achouri Y, Carre D, Girard J, et al. Sterol regulatory element binding protein-1c expression and action in rat muscles: insulin-like effects on the control of glycolytic and lipogenic enzymes and UCP3 gene expression. Diabetes 2002; 51: 1722–1728.
  • 24
    Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 2000; 350: 389–393.
  • 25
    Magana MM, Osborne TF. Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem 1996; 271: 32689–32694.
  • 26
    Magana MM, Lin SS, Dooley KA, Osborne TF. Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins. J Lipid Res 1997; 38: 1630–1638.
  • 27
    Bene H, Lasky D, Ntambi JM. Cloning and characterization of the human stearoyl-CoA desaturase gene promoter: transcriptional activation by sterol regulatory element binding protein and repression by polyunsaturated fatty acids and cholesterol. Biochem Biophys Res Commun 2001; 284: 1194–1198.
  • 28
    Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 1997; 46: 1768–1774.
  • 29
    Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997; 46: 983–988.
  • 30
    Arner P. Insulin resistance in type 2 diabetes: role of fatty acids. Diabetes Metab Res Rev 2002; 18: S5–S9.
    Direct Link:
  • 31
    Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 2003; 278: 34268–34276.
  • 32
    Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 2003; 111: 737–747.
  • 33
    Pickavance LC, Buckingham RE, Wilding JP. Insulin-sensitizing action of rosiglitazone is enhanced by preventing hyperphagia. Diabetes Obes Metab 2001; 3: 171–180.
    Direct Link:
  • 34
    Emilsson V, O'Dowd J, Wang S, Liu YL, Sennitt M, Heyman R, et al. The effects of rexinoids and rosiglitazone on body weight and uncoupling protein isoform expression in the Zucker fa/fa rat. Metabolism 2000; 49: 1610–1615.
View Full Article (HTML) Get PDF (617K)