Liver Injury and Regeneration

You have full text access to this OnlineOpen article

Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis†

  1. Kanji Yamaguchi1,
  2. Liu Yang1,
  3. Shannon McCall2,
  4. Jiawen Huang1,
  5. Xing Xian Yu3,
  6. Sanjay K. Pandey3,
  7. Sanjay Bhanot3,
  8. Brett P. Monia3,
  9. Yin-Xiong Li1,
  10. Anna Mae Diehl1,‡,*

Article first published online: 13 NOV 2007

DOI: 10.1002/hep.21988

Issue

Hepatology

Hepatology

Volume 47, Issue 2, pages 625–635, February 2008

Additional Information

How to Cite

Yamaguchi, K., Yang, L., McCall, S., Huang, J., Yu, X. X., Pandey, S. K., Bhanot, S., Monia, B. P., Li, Y.-X. and Diehl, A. M. (2008), Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology, 47: 625–635. doi: 10.1002/hep.21988

Author Information

  1. 1

    Division of Gastroenterology, Duke University Medical Center, Durham, NC

  2. 2

    Department of Pathology, Duke University Medical Center, Durham, NC

  3. 3

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

  1. ‡

    fax: 919-684-4183

*Duke University, Division of Gastroenterology, Ste 1073, GSRB #1 595 LaSalle Street, Durham, NC 27710

  1. †

    Potential conflict of interest: Drs. Monia, Bhanot, and Yu own stock in Isis Pharmaceuticals.

Publication History

  1. Issue published online: 26 JAN 2008
  2. Article first published online: 13 NOV 2007
  3. Manuscript Accepted: 13 AUG 2007
  4. Manuscript Received: 8 MAY 2007

Funded by

  • NIH/NIDDK. Grant Number: RO1DK53792

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (3279K)

References

  • 1
    Friedman SL. The cellular basis of hepatic fibrosis: mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828–1835.
  • 2
    Friedman SL, Wei S, Blaner WS. Retinol release by activated rat hepatic lipocytes: regulation by Kupffer cell-conditioned medium and PDGF. Am J Physiol 1993; 264: G947–G952.
  • 3
    Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996; 10: 940–954.
  • 4
    Hellemans K, Verbuyst P, Quartier E, Schuit F, Rombouts K, Chandraaratna RA, et al. Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids. HEPATOLOGY 2004; 39: 97–108.
    Direct Link:
  • 5
    Moriwaki H, Blaner WS, Piantedosi R, Goodman DS. Effects of dietary retinoid and triglyceride on the lipid composition of rat liver stellate cells and stellate cell lipid droplets. J Lipid Res 1988; 29: 1523–1534.
  • 6
    Ross AC, Zolfaghari R. Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status. J Nutr 2004; 134: 269S–275S.
  • 7
    Liu L, Gudas LJ. Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency. J Biol Chem 2005; 280: 40226–40234.
  • 8
    O'Byrne SM, Wongsirriroj N, Libien J, Vogel S, Goldberg IJ, Baehr W, et al. Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT). J Biol Chem 2005; 280: 35647–35657.
  • 9
    Weiner FR, Blaner WS, Czaja MJ, Shah A, Geerts A. Ito cell expression of a nuclear retinoic acid receptor. HEPATOLOGY 1992; 15: 336–342.
    Direct Link:
  • 10
    Ohata M, Lin M, Satre M, Tsukamoto H. Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis. Am J Physiol 1997; 272: G589–G596.
  • 11
    deThe V, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 1990; 343: 177–180.
  • 12
    Petkovich M, Brand NJ, Drust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 1987; 330: 444–450.
  • 13
    Wang L, Attard FA, Tankersley LR, Potter JJ, Mezey E. Effect of retinoic acid on the enhancing effect of acetaldehyde on mouse type I collagen expression. Arch Biochem Biophys 2000; 376: 191–198.
  • 14
    Wang L, Tankersley LR, Tang M, Potter JJ, Mezey E. Regulation of the murine alpha2(I)collagen promoter by retinoic acid and retinoid X receptors. Arch Biochem Biophys 2002; 401: 262–270.
  • 15
    Wang L, Tankersley LR, Tang M, Potter JJ, Mezey E. Regulation of alpha2(I)collagen expression in stellate cells by retinoic acid and retinoid X receptors through interactions with their cofactors. Arch Biochem Biophys 2004; 428: 92–98.
  • 16
    Fortuna VA, Trugo LC, Borojevic R. Acyl-CoA:retinol acyltransferase (ARAT) and lecithin:retinol acyltransferase (LRAT) activation during the lipocyte phenotype induction in hepatic stellate cells. J Nutr Biochem 2001; 12: 610–621.
  • 17
    Yen CL, Monetti M, Burri BJ, Farese RVJ. The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J Lipid Res 2005; 46: 1502–1511.
  • 18
    Chen HC, Farese RVJ. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol 2005; 25: 482–486.
  • 19
    Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, et al. Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol 2004; 287: G1035–G1043.
  • 20
    Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. HEPATOLOGY 2007; 45: 1366–1374.
    Direct Link:
  • 21
    Choi SS, Sicklick JK, Ma Q, Yang L, Huang J, Qi Y, et al. Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice. HEPATOLOGY 2006; 44: 1267–1277.
    Direct Link:
  • 22
    Suzuki A, McCall S, Choi SS, Sicklick JK, Huang J, Qi Y, et al. Interleukin-15 increases hepatic regenerative activity. J Hepatol 2006; 45: 410–418.
  • 23
    Sicklick JK, Li YX, Choi SS, Qi Y, Chen W, Bustamante M, et al. Role for Hedgehog signaling in hepatic stellate cell activation and viability. Lab Invest 2005; 85: 1368–1380.
  • 24
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and th s(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.
  • 25
    Yata T, Gotwals P, Koteliansky V, Rockey DC. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy. HEPATOLOGY 2002; 35: 1022–1030.
    Direct Link:
  • 26
    Satre MA, Ugen KE, Kochlar DM. Developmental changes in endogenous retinoids during preganncy and embryogenesis in the mouse. Biol Reprod 1992; 46: 802–810.
  • 27
    Ramos-Lledo P, Vera S, San Andres MP. Determination of viatmins A and E in milk samples by fluorescence in micellar media. Fresenius J Anal Chem 2001; 369: 91–95.
  • 28
    Leon-Ruiz V, Vera S, San Andres MP. Validation of a screening method for the simultaneous identification of fat-soluble and water-soluble vitamins (A, E, B1, B2 and B6) in an aqueous micellar medium of hexadencnyltrimethylammonium chloride. Anal Bioanal Chem 2005; 381: 1568–1575.
  • 29
    Brunt EM, Janney CG, DiBisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastoenterol 1999; 94: 2467–2474.
    Direct Link:
  • 30
    Blomhoff R, Rasmussen M, Nilsson A, Norum KR, Berg T, Blaner WS, et al. Hepatic retinol metabolism: distribution of retinoids, enzymes and binding proteins in isolated rat liver cells. J Biol Chem 1985; 260: 13560–13565.
  • 31
    Shimada T, Ross AC, Muccio DD, Brouillette WJ, Shealy YF. Regulation of hepatic lecithin:retinol acyltransferase activity by retinoic acid receptor-selective retinoids. Arch Biochem Biophys 1997; 344: 220–227.
  • 32
    Kurlandsky SB, Duell EA, Kang S, Voorhees JJ, Fisher GJ. Auto-regulation of retinoic acid biosynthesis throught regulation of retionl esterification in human keratinocytes. J Biol Chem 1996; 271: 15346–15352.
  • 33
    Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 2007; 129: 723–733.
  • 34
    Vincente CP, Fortuna VA, Margis R, Trugo LC, Borojevic R. Retinol uptake and metabolism, and cellular retinol binding protein expression in an in vitro model of hepatic stellate cells. Mol Cell Biochem 1998; 187: 11–21.
  • 35
    Ghyselinck NB, Bavik C, Sapin V, Mark M, Bonnier D, Hindelang C, et al. Cellular retinol-binding protein I is essential for viatmin A homeostasis. EMBO J 1999; 18: 4903–4914.
  • 36
    Randolph RK, Winkler KE, Ross AC. Fatty acyl CoA-dependent and -independent retinol esterification by rat liver and lactating mammary gland microsomes. Arch Biochem Biophys 1991; 288: 500–508.
  • 37
    Matsuura T, Nagamori S, Hasumura S, Sujino H, Niiya M, Shimizu K. Regulation of vitamin A transport into cultured stellate cells of rat liver: studies by anchored cell analysis and sorting systems. Exp Cell Res 1993; 209: 33–37.
  • 38
    Choi CS, Savage DB, Kulkarni S, Yu XX, Liu ZS, Morino K, et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 2007; 282: 22678–22688.
  • 39
    Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S, et al. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem 2007; 18: 184–195.
  • 40
    Yu YH, Ginsberg HN. The role of acyl-CoA:diacylglycerol acyltransferase (DGAT) in enerfy metabolism. Ann Med 2004; 36: 252–261.
  • 41
    Yamazaki T, Sasaki E, Kakinuma C, Yano T, Miura S, Ezaki O. Increased very low density lipoprotein secretion and gonadal fat mass in mice overexpressing liver DGAT1. J Biol Chem 2005; 280: 21506–21514.
  • 42
    Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. HEPATOLOGY 2005; 42: 362–371.
    Direct Link:
View Full Article (HTML) Get PDF (3279K)