Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor

Colell, Anna; Garcı́a-Ruiz, Carmen; Miranda, Merce; Ardite, Esther; Marı́, Montserrat; Morales, Albert; Corrales, Fernando J.; Kaplowitz, Neil; Fernández-Checa, José C.

doi:10.1016/s0016-5085(98)70034-4

Cited by 340 publications

(278 citation statements)

References 40 publications

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“…Selective depletion of the hepatocyte mitochondrial GSH pool by alcohol and the subsequent sensitization to TNF induced cytotoxicity has been postulated to be one etiologic factor in the development of ALD [7,8]. Our current study is the first to report that chronic alcohol consumption caused depletion of the mitochondrial SAM pool.…”

Section: Discussionsupporting

confidence: 49%

“…Mitochondrial dysfunction has been implicated in a variety of liver diseases including ALD [7,8,[36][37][38][39][40]. Selective depletion of the hepatocyte mitochondrial GSH pool by alcohol and the subsequent sensitization to TNF induced cytotoxicity has been postulated to be one etiologic factor in the development of ALD [7,8].…”

Section: Discussionmentioning

confidence: 99%

“…Phosphatidylcholine is the major phospholipid component in the mitochondrial membrane, and its composition plays a critical role in maintaining membrane fluidity and integrity [41,42]. The influence of alcohol on the mitochondrial membrane has been reported and postulated to be one of mechanisms explaining alcohol-induced selective mitochondrial GSH depletion and sensitization to TNF hepatotoxicity [7,43].Studies using mitochondria from rat hepatocytes have shown that inhibition of the mitochondrial SAM transporter inhibited incorporation of the methyl group from SAM into phospholipid [24]. Therefore, it is possible that the depletion of the mitochondrial SAM pool by SAH causes the loss of integrity of the mitochondrial membrane leading to the sensitization to TNF induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Several factors have been demonstrated to sensitize hepatocytes to TNF cytotoxicity. Some of these factors include agents inhibiting protein synthesis or inducing transcriptional arrest [6]; agents causing total GSH depletion or selective mitochondrial GSH depletion [7,8]; and agents inhibiting proteosome function [9].…”

Section: Introductionmentioning

confidence: 99%

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Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: Possible involvement of mitochondrial S-adenosylmethionine transport

Song

Zhou

Song

et al. 2007

Biochemical Pharmacology

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Hepatocytes are resistant to tumor necrosis factor-α-(TNF) induced killing/apoptosis under normal circumstances, but primary hepatocytes from rats chronically fed alcohol have increased TNF cytotoxicity. Therefore, there must be mechanism(s) by which alcohol exposure "sensitizes" to TNF hepatotoxicity. Abnormal metabolism of methionine and Sadenosylmethionine (SAM) are well documented acquired metabolic abnormalities in ALD. Sadenosylhomocysteine (SAH) is the product of SAM in hepatic transmethylation reactions, and SAH hydrolase (SAHH) is the only enzyme to metabolize SAH to homocysteine and adenosine. Our previous studies demonstrated that chronic intracellular accumulation of SAH sensitized hepatocytes to TNF cytotoxicity in vitro. In the current study, we extended our previous observations by further characterizing the effects of chronic alcohol intake on mitochondrial SAM levels in liver and examining its possible involvement in SAH sensitization to TNF hepatotoxicity. Chronic alcohol consumption in mice not only increased cytosolic SAH levels, but also decreased mitochondrial SAM concentration, leading to decreased mitochondrial SAM to SAH ratio. Moreover, accumulation of hepatic SAH induced by administration of 3-deazaadenosine (DZA-a potent inhibitor of SAHH) enhanced lipopolysaccharide (LPS) /TNF hepatotoxicity in mice in vivo. Inhibition of SAHH by DZA resulted not only in accumulation of cytoplasmic SAH, but also in depletion of the mitochondrial SAM pool. Further studies using mitochondrial SAM transporter inhibitors showed that inhibition of SAM transport into mitochondria sensitized HepG2 cells to TNF cytotoxicity. In conclusion, our results demonstrate that depletion of the mitochondrial SAM pool by SAH, which is elevated during chronic alcohol consumption, plays a critical role in SAH induced sensitization to TNF hepatotoxicity.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: Possible involvement of mitochondrial S-adenosylmethionine transport

Song

Zhou

Song

et al. 2007

Biochemical Pharmacology

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“…Studies by Fernandez-Checa and colleagues demonstrated that chronic alcohol consumption depletes mitochondrial GSH [75] and treatments that prevent the loss in inner membrane fluidity maintain GSH uptake and preserve mitochondrial GSH levels in liver of alcohol-fed animals [76,77]. Importantly, it is proposed that loss of mitochondrial GSH sensitizes hepatocytes from alcohol-fed animals to TNFα induced cell death [78,79], specifically when mitochondria are "loaded" with free cholesterol [80]. In contrast, several studies have shown that mitochondrial GSH depletion may not be a consistent outcome following chronic alcohol consumption as studies have shown increased mitochondrial GSH in response to alcohol consumption [81][82][83][84].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

382

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Ethanol Metabolism and Pathogenesis of Alcoholic Liver Injury

Stewart¹,

Day²

2007

Textbook of Hepatology

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Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor

Cited by 340 publications

References 40 publications

Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: Possible involvement of mitochondrial S-adenosylmethionine transport

Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: Possible involvement of mitochondrial S-adenosylmethionine transport

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Ethanol Metabolism and Pathogenesis of Alcoholic Liver Injury

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