<i>S</i>-adenosylmethionine deficiency and TNF-α  in lipopolysaccharide-induced hepatic injury

Chawla, Rajender K.; Watson, Walter H.; Eastin, Charles E.; Lee, Eun Y.; Schmidt, Jack; McClain, Craig J.

doi:10.1152/ajpgi.1998.275.1.g125

Cited by 83 publications

(123 citation statements)

References 26 publications

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“…We observed significantly increased (7.7-fold) gene expression of TNF-␣ with RT-PCR in the livers of MCD animals consistent with increased TNF-␣ previously reported by us in MCD rats [3]. TNF-␣ is mainly released from sensitized Kupffer cells and damages hepatocytes.…”

Section: Discussionsupporting

confidence: 91%

“…SAMe deficiency is often associated with GSH deficiency [3,8], since SAMe enhances hepatic GSH. Endogenous liver SAMe is also a substrate for the de novo biosynthesis of choline.…”

Section: Discussionmentioning

confidence: 99%

“…Endogenous liver SAMe is also a substrate for the de novo biosynthesis of choline. SAMe deficiency occurs in liver injuries such as alcoholic [3] and acetaminophen overdoses [12], and these injuries may be attenuated by the administration of SAMe.…”

Section: Discussionmentioning

confidence: 99%

“…The etiology of NASH remains elusive, but most investigators agree that a baseline of steatosis requires a second "hit" capable of inducing inflammation, fibrosis, or necrosis in order to develop NASH. Oxidative stress, with the accumulation of lipid peroxidation products, mitochondrial dysfunction [3][4][5], endotoxins derived from the gut, and inflammatory cytokines in the liver have been implicated in the initiation of liver injury in NASH [5][6][7][8]. Glutathione (GSH) is a major endogenous antioxidant, and GSH prodrugs are attractive therapy for many forms of liver injury.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups ( p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-␣1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and TGF-␤) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. C

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Section: Discussionsupporting

confidence: 91%

“…SAMe deficiency is often associated with GSH deficiency [3,8], since SAMe enhances hepatic GSH. Endogenous liver SAMe is also a substrate for the de novo biosynthesis of choline.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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“…Oxidant-induced hepatocellular necrosis is the net result of enhanced generation of reactive oxidant species and depletion of antioxidants, in particular mitochondrial GSH (54). Disordered methionine metabolism is an established feature of experimental and clinical alcoholic liver disease and could contribute to its pathogenesis through effects on oxidant stress (28) and on DNA integrity (16,26,55).…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Halsted

Villanueva

Devlin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

185

179

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Alcoholic liver disease is associated with abnormal hepatic methionine metabolism and folate deficiency. Because folate is integral to the methionine cycle, its deficiency could promote alcoholic liver disease by enhancing ethanol-induced perturbations of hepatic methionine metabolism and DNA damage. We grouped 24 juvenile micropigs to receive folate-sufficient (FS) or folate-depleted (FD) diets or the same diets containing 40% of energy as ethanol (FSE and FDE) for 14 wk, and the significance of differences among the groups was determined by ANOVA. Plasma homocysteine levels were increased in all experimental groups from 6 wk onward and were greatest in FDE. Ethanol feeding reduced liver methionine synthase activity, S-adenosylmethionine (SAM), and glutathione, and elevated plasma malondialdehyde (MDA) and alanine transaminase. Folate deficiency decreased liver folate levels and increased global DNA hypomethylation. Ethanol feeding and folate deficiency acted together to decrease the liver SAM͞S-adenosylhomocysteine (SAH) ratio and to increase liver SAH, DNA strand breaks, urinary 8-oxo-2 -deoxyguanosine [oxo(8)dG]͞mg of creatinine, plasma homocysteine, and aspartate transaminase by more than 8-fold. Liver SAM correlated positively with glutathione, which correlated negatively with plasma MDA and urinary oxo(8)dG. Liver SAM͞SAH correlated negatively with DNA strand breaks, which correlated with urinary oxo(8)dG. Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MDA. Steatohepatitis occurred in five of six pigs in FDE but not in the other groups. In summary, folate deficiency enhances perturbations in hepatic methionine metabolism and DNA damage while promoting alcoholic liver injury. F olate deficiency is among the most common nutritional abnormalities in chronic alcoholic patients, especially in those who have developed alcoholic liver injury (1-5). In addition to poor diet, folate deficiency in chronic alcoholism can be ascribed to decreased intestinal absorption and hepatic uptake, increased renal excretion, and increased oxidative cleavage of the folate molecule (6-12). Folate in its 5-methyltetrahydrofolate (5-MTHF) form is integral to methionine metabolism. Folate deficiency perturbs hepatic methionine metabolism (13,14), which is associated with DNA nucleotide imbalance and increased hepatocellular apoptosis in experimental animals fed folate-deficient (FD) diets or exposed to chronic ethanol (15,16).Hepatic methionine metabolism is regulated by the availability of dietary and endogenous folate that appears in the circulation as 5-MTHF and is the substrate with cofactor vitamin B 12 for the methionine synthase (MS) reaction that generates methionine from homocysteine (Hcy) (see supporting information, which is published on the PNAS web site, www.pnas.org). In the alternate salvage pathway for methionine synthesis, choline is the precursor of betaine, which is the substrate for betaine homocysteine methyltransferase (BHMT). The methionine adeno...

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5′-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes†

et al. 2004

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5-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-␣ (TNF-␣), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IB␣) degradation, and nuclear factor B (NFB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases.

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S-adenosylmethionine deficiency and TNF-α in lipopolysaccharide-induced hepatic injury

Cited by 83 publications

References 26 publications

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

5′-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes†

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