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Digestive Diseases and Sciences

, Volume 53, Issue 3, pp 767–776 | Cite as

Methionine Deficiency and Hepatic Injury in a Dietary Steatohepatitis Model

  • Helieh S. Oz
  • Theresa S. Chen
  • Manuela Neuman
Original Paper

Abstract

Methionine (Meth) is an essential amino acid involved in DNA methylation and glutathione biosynthesis. We examined the effect of Meth on the development of steatohepatitis. Rats were fed (five weeks) amino acid-based Meth-choline-sufficient (A-MCS) or total deficient (MCD) diets and gavaged daily (two weeks) with vehicle (B-vehicle/MCD), or Meth replacement (C-Meth/MCD). To assess the effect of short-term deficiency, after three weeks one MCS group was fed a deficient diet (D-MCS/MCD). Animals fed the deficient diet for two weeks lost (29%) weight and after five weeks weighed one third as much as those on the sufficient diet, and also developed anemia (P < 0.01). Hepatic transaminases progressively increased from two to five weeks (P < 0.01), leading to severe hepatic pathology. Meth administration normalized hematocrit, improved weight (P < 0.05), and suppressed abnormal enzymes activities (P < 0.01). Meth administration improved blood and hepatic glutathione (GSH), S-adenosylmethionine (SAMe), and hepatic lesions (P < 0.01). The deficient diet significantly upregulated proinflammatory and fibrotic genes, which was ameliorated by Meth administration. These data support a pivotal role for methionine in the pathogenesis of the dietary model of Meth-choline-deficient (MCD) steatohepatitis (NASH).

Keywords

Methionine MCD MCS diets 

Abbreviations

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

BCP

Bromochlorophenol

cDNA

Complementary DNA

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

GSH

Reduced glutathione

GSSG

Oxidized glutathione

IL-1β- IL-6

Interleukin-1beta and interleukin-6

MCD

Methionine-choline-deficient diet

MCS

Methionine-choline-sufficient diet

MMPs

Tissue matrix metalloproteinases

Meth

Methionine

mRNA

Messenger RNA

NAFL

Non-alcoholic fatty liver

NASH

Non-alcoholic steatohepatitis

PCR

Polymerase chain reaction

SAMe

S-adenosylmethionine

SOCS

Silencing suppressor of cytokine signaling

TGF-β

Transforming growth factor beta

TNF-α

Tumor necrosis factor alpha

Notes

Acknowledgements

This study was supported by National Institutes of Health grant NCAM AT1490 (H.S. Oz). Marcia C. Liu provided technical assistance.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Helieh S. Oz
    • 1
  • Theresa S. Chen
    • 2
  • Manuela Neuman
    • 3
  1. 1.Center for the Oral Health Research, Department of Internal MedicineUniversity of Kentucky Medical CenterLexingtonUSA
  2. 2.Department of Pharmacology and ToxicologyUniversity of Louisville Medical SchoolLouisvilleUSA
  3. 3.In Vitro Drug Safety and Biotechnology, Department of Pharmacology & Institute of Drug ResearchUniversity of TorontoTorontoCanada

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