How Is the Liver Primed or Sensitized for Alcoholic Liver Disease?

Tsukamoto, Hidekazu; Takei, Yoshiyuki; McClain, Craig J.; Hill, Daniell B.; Schmidt, Jack; Deaciuc, Ion V.; Colell, Anna; Garcı́a-Ruiz, Carmen; Kaplowitz, Neil; Fernández‐Checa, José C.; Yokoyama, Hirokazu; Okamura, Yukishige; Nakamura, Yuji; Ishii, Hiromasa; Chawla, Rajender K.; Barve, Shirish; Joshi‐Barve, Swati; Watson, Walter H.; Nelson, William G.; Lin, Mao; Ohata, Mitsuru; Motomura, Kenta; Enomoto, Nobuyuki; Ikejima, Kenichi; Kitamura, Tsuneo; Oide, Hirosumi; Hirose, Miyoko; Bradford, Blair U.; Rivera, Chantal A.; Kono, Hiroshi; Peter, Soumia; Yamashina, Shunhei; Konno, Akira; Ishikawa, Masatoshi; Shimizu, Hirotomo; Sato, Nobuhiro; Thurman, Ronald G.

doi:10.1111/j.1530-0277.2001.tb02393.x

Cited by 56 publications

(49 citation statements)

References 75 publications

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“…In contrast, in RAW macrophages that reportedly be- have similar to Kupffer cells, P. acnes failed to prime for LPS-induced MD-2 and CD14 increase. 34 These data suggest that hepatocytes may represent the primary cellular source for the up-regulation of MD-2 and CD14 levels seen in vivo after P. acnes priming and LPS stimulation in the liver. Increased expression of CD14 has previously been shown in P. acnes-induced sensitization to LPS.…”

Section: Discussionmentioning

confidence: 88%

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

et al. 2004

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Lipopolysaccharide (LPS) triggers cytokine production through Toll-like receptor 4 (TLR4), which shares downstream signaling pathways with TLR2. We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands. Stock LPS induced interleukin 8 in both TLR4-and TLR2-expressing human embryonic kidney (HEK) 293 cells. Purified LPS (TLR4 ligand) activated HEK/TLR4 cells, while peptidoglycan and lipoteichoic acid (TLR2 ligands) activated HEK/TLR2 cells, respectively. In mice, P. acnes priming resulted in increased liver messenger RNA (mRNA) and serum levels of tumor necrosis factor ␣, interleukin 12, and interferon ␥ (IFN-␥) by both stock LPS and purified LPS challenges compared with nonprimed controls. In contrast, P. acnes failed to sensitize to TLR2 ligands (peptidoglycan ؉ lipoteichoic acid). In the liver, P. acnes-priming was associated with up-regulation of TLR4 and MD-2 proteins, and subsequent LPS challenge further increased MD-2 and CD14 mRNA levels. The lack of sensitization to TLR2 ligands by P. acnes correlated with no increase in hepatic TLR1 or TLR6 mRNA. In vitro, P. acnes pretreatment desensitized RAW macrophages to a secondary stimulation via both TLR2 and TLR4. However, IFN-␥ could selectively prevent desensitization to TLR4 but not to TLR2 ligands. Furthermore, P. acnes induced production of IFN-␥ in vivo as well as in isolated splenocytes. In vitro, P. acnes-primed Hepa 1-6 hepatocytes but not RAW macrophages produced increased MD-2 and CD14 mRNA levels after an LPS challenge. In conclusion, P. acnes priming to selective TLR4-mediated liver injury is associated with up-regulation of TLR4 and MD-2 and is likely to involve IFN-␥ and prevent TLR4 desensitization by P. acnes. (HEPATOLOGY 2004;40:555-564.)

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Section: Discussionmentioning

confidence: 88%

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

et al. 2004

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“…The detrimental effects of ethanol are partly mediated through increased oxidative/nitrosative stress resulting from the enhanced activity of a variety of proteins including CYP2E1, NADPH oxidase, xanthine oxidase, and inducible NOS, with reduced levels of GSH and other antioxidants. [1][2][3] Increased nitric oxide and superoxide, which can be also produced by resident macrophages (Kupffer cells) and infiltrating leukocytes (neutrophils) in alcohol-exposed animals, 2,3 can lead to the elevated production of peroxynitrite, which may cause cellular damage. 16,[34][35][36] In fact, the immunoblot results showed increased CD16, a marker protein for neutrophils, in the alcohol-exposed rats ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…16 In fact, many cellular proteins have been shown to be modified by peroxynitrite, leading to often deleterious alterations in their physiological functions. 17,18 Chronic alcohol exposure reduces the levels of oxidation scavengers such as glutathione and other antioxidants [1][2][3] and the activity of certain protective enzymes such as isocitrate dehydrogenase 14 and peroxiredoxin. 19 Our recent study showed that the activity of mitochondrial aldehyde dehydrogenase 2 (ALDH2) was reversibly inhibited through S-nitrosylation of its cysteine residues in the presence of various nitric oxide (NO) donors.…”

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confidence: 99%

Inactivation of oxidized andS-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats

et al. 2006

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Increased oxidative/nitrosative stress is a major contributing factor to alcohol-mediated mitochondrial dysfunction. However, which mitochondrial proteins are oxidatively modified under alcohol-induced oxidative/nitrosative stress is poorly understood. The aim of this study was to systematically investigate oxidized and/or S-nitrosylated mitochondrial proteins and to use a biotin-N-maleimide probe to evaluate their inactivation in alcoholic fatty livers of rats. Binge or chronic alcohol exposure significantly elevated nitric oxide, inducible nitric oxide synthase, and ethanol-inducible CYP2E1. The biotin-N-maleimide-labeled oxidized and/or S-nitrosylated mitochondrial proteins from pair-fed controls or alcohol-fed rat livers were subsequently purified with streptavidin-agarose. The overall patterns of oxidized and/or S-nitrosylated proteins resolved by 2-dimensional polyacrylamide gel electrophoresis were very similar in the chronic and binge alcohol treatment groups. Seventy-nine proteins that displayed differential spot intensities from those of control rats were identified by mass spectrometry. These include mitochondrial aldehyde dehydrogenase 2 (ALDH2), ATP synthase, acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, and many proteins involved in chaperone activity, mitochondrial electron transfer, and ion transport. The activity of 3-ketoacyl-CoA thiolase involved in mitochondrial ␤-oxidation of fatty acids was significantly inhibited in alcohol-exposed rat livers, consistent with hepatic fat accumulation, as determined by biochemical and histological analyses. Measurement of activity and immunoblot results showed that ALDH2 and ATP synthase were also inhibited through oxidative modification of their cysteine or tyrosine residues in alcoholic fatty livers of rats. In conclusion, our results help to explain the underlying mechanism for mitochondrial dysfunction and increased susceptibility to alcohol-mediated liver damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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“…One complication in this central role for TNFα is that hepatocytes are normally resistant to TNFα induced toxicity. This led to the hypothesis that besides elevating TNFα, alcohol somehow sensitizes or primes the liver to become susceptible to TNFα (201,202). Known factors which sensitize the liver to TNFα are inhibitors of mRNA or protein synthesis, which likely prevent the synthesis of protective factors, inhibition of NF-κB activation to lower synthesis of such protective factors, depletion of GSH, especially mitochondrial GSH, lowering of s-adenosyl methionine (SAM) coupled to elevation of S-adenosyl homocysteine (SAH) i.e.…”

Section: Lps/tnfα-cyp2e1 Interactionsmentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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How Is the Liver Primed or Sensitized for Alcoholic Liver Disease?

Cited by 56 publications

References 75 publications

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

Inactivation of oxidized andS-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats

CYP2E1 and oxidative liver injury by alcohol

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