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

Publication ,  Journal Article
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
Published in: Hepatology
February 2008

UNLABELLED: Retinyl ester (RE) stores decrease during hepatic stellate cell (HSC) activation and liver fibrosis. Although retinol esterification is mostly catalyzed by lecithin:retinol acyltransferase (LRAT), diacylglycerol acyltransferase (DGAT)1 also does this. In previous reports, LRAT(-/-) mice had reduced hepatic RE but neither excessive HSC activation nor liver fibrosis, and DGAT1(-/-) mice had increased liver levels of RE and retinol. We sought to clarify the role of DGAT1 in liver fibrosis. Expression of DGAT1/2 was compared by real time PCR in freshly isolated, primary mouse HSCs and hepatocytes. To induce nonalcoholic steatohepatitis (NASH) and liver fibrosis, adult male db/db mice were fed methionine choline-deficient (MCD) diets. Half were treated with DGAT1 antisense oligonucleotide (ASO); the rest were injected with saline. Results were compared with chow-fed controls. Inhibition of DGAT1 in liver had no effect on hepatic triglyceride content or liver necroinflammation but reduced HSC activation and liver fibrosis in mice with NASH. To evaluate the role of DGAT1 in HSC activation, HSC were isolated from healthy rats treated with DGAT1 ASO or saline. DGAT1 was expressed at relatively high levels in HSCs. HSC isolated from DGAT1 ASO-treated rats had reduced DGAT1 expression and increased messenger RNA (mRNA) levels of LRAT and cellular retinol binding protein-1. During culture, they retained more vitamin A, had repressed collagen a2 (I) transcriptional activity, and expressed less collagen a1 (I) and a2 (I) mRNA. CONCLUSION: DGAT1 may be a therapeutic target in NASH because inhibiting DGAT1 favorably altered. HSC retinoid homeostasis and inhibited hepatic fibrosis in mice with NASH.

Duke Scholars

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

February 2008

Volume

47

Issue

2

Start / End Page

625 / 635

Location

United States

Related Subject Headings

  • Reverse Transcriptase Polymerase Chain Reaction
  • Oligonucleotides, Antisense
  • Mice, Inbred Strains
  • Mice
  • Male
  • Liver Cirrhosis
  • Hepatitis
  • Gastroenterology & Hepatology
  • Fatty Liver
  • Disease Models, Animal
 

Citation

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Yamaguchi, K., Yang, L., McCall, S., Huang, J., Yu, X. X., Pandey, S. K., … Diehl, A. M. (2008). Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology, 47(2), 625–635. https://doi.org/10.1002/hep.21988
Yamaguchi, Kanji, Liu Yang, Shannon McCall, Jiawen Huang, Xing Xian Yu, Sanjay K. Pandey, Sanjay Bhanot, Brett P. Monia, Yin-Xiong Li, and Anna Mae Diehl. “Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis.Hepatology 47, no. 2 (February 2008): 625–35. https://doi.org/10.1002/hep.21988.
Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, et al. Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology. 2008 Feb;47(2):625–35.
Yamaguchi, Kanji, et al. “Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis.Hepatology, vol. 47, no. 2, Feb. 2008, pp. 625–35. Pubmed, doi:10.1002/hep.21988.
Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li Y-X, Diehl AM. Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology. 2008 Feb;47(2):625–635.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

February 2008

Volume

47

Issue

2

Start / End Page

625 / 635

Location

United States

Related Subject Headings

  • Reverse Transcriptase Polymerase Chain Reaction
  • Oligonucleotides, Antisense
  • Mice, Inbred Strains
  • Mice
  • Male
  • Liver Cirrhosis
  • Hepatitis
  • Gastroenterology & Hepatology
  • Fatty Liver
  • Disease Models, Animal