Intrahepatic accumulation of nitrotyrosine in chronic viral hepatitis is associated with histological severity of liver disease

García‐Monzón, Carmelo; Majano, Pedro L.; Zubia, I Aguirre; Sanz, Patricia; Apolinario, A.; Moreno–Otero, Ricardo

doi:10.1016/s0168-8278(00)80080-x

Cited by 101 publications

(62 citation statements)

References 33 publications

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“…An increased dietary supply of fat or carbohydrates to the liver may promote steatosis by increasing hepatic lipid uptake. In this pathway, oxidative stress appears to play a key role in the pathogenesis of NASH [10,20], and nitric oxide may potentiate cytotoxicity through its reaction with superoxide anion and formation of nitrotyrosine [13,14]. The finding that an abnormal intrahepatic accumulation of nitrotyrosine is associated with the histological severity of NASH strongly suggests that NO-related oxidative injury may play a significant role in the pathogenesis of this liver disease [14].…”

Section: Discussionmentioning

confidence: 99%

Inducible Nitric Oxide Distribution in the Fatty Liver of a Mouse with High Fat Diet-Induced Obesity

Chae

2010

Exp. Anim.

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Abstract:Obesity is a condition of abnormal adipose tissue storage and recently it has been recognized as a major factor in metabolic syndrome. High-fat diet-induced obesity in the C57BL/6 mouse is an important animal model because of its similarities with human obesity. The aim of the present study was to estimate obesity, liver injury and steatohepatitis, and the distribution of inducible nitric oxide synthase (iNOS) in mice with high-fat diet induced obesity. Three-week-old male C57BL/6J mice were fed either a high-fat diet (D-60: 60 kcal% fat, or D-45: 45 kcal% fat) or a normal diet (D-10: 10 kcal% fat) for 15 weeks. Oral glucose tolerance tests and intraperitoneal glucose tolerance tests showed that the D-60 mice had severely impaired glucose tolerance. In serum chemistry values and histopathological lesions, the D-60 group showed severe steatohepatitis. A distinct positive signal for iNOS was detected by immunohistochemistry in the cytoplasm of hepatocytes around the central vein in the D-45 and D-60 groups. Serum insulin levels and insulin immunohistochemistry in the pancreas showed pancreatic injury and insulin resistance in the D-60 group. We observed the presence of more iNOS in the high-fat diet-induced obese mouse, which has characteristics of nonalcoholic steatohepatitis (NASH) and diabetes, and expect that these background pathological data will be useful in research on obesity, diabetes mellitus, and non-alcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 99%

Inducible Nitric Oxide Distribution in the Fatty Liver of a Mouse with High Fat Diet-Induced Obesity

Chae

2010

Exp. Anim.

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“…In addition, a significant association between the intrahepatic level of 3-nitrotyrosine and the severity of viral liver diseases has been found. 3 Tyrosine nitration not only serves as an important "dosimeter" or "biomarker" of reactive nitrogen species production and reactivity but also has been shown to compromise the catalytic function of cytochrome c,4 glutathione S-transferase,5 and NADH:ubiquinone reductase. 6 Myeloperoxidase (MPO) can also catalyze the formation of 3-nitrotyrosine using NO2 as a substrate.…”

mentioning

confidence: 99%

Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions

Eiserich

Ansari

et al. 2003

Hepatology

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Previous studies have suggested that increased nitric oxide (NO)-mediated products are found in the livers of subjects with primary biliary cirrhosis (PBC), but the mechanisms involved remain enigmatic. We took advantage of immunohistochemistry and several unique monoclonal antibodies to study inflammatory cells responsible for the generation of NO, the enzymes responsible for NO production, the expression of 3-nitrOtyrOSine, and the presence of CD68' and/or myeloperoxidase (MPO) + cells. We examined a total of 1 13 liver specimens, including 64 with PBC, 19 with primary sclerosing cholangitis (PSC), 6 with non-A, non-B hepatitis, 6 with alcoholic liver disease, 4 with cryptogenic cirrhosis, 4 with biliary atresia, and 10 normal subjects. Twentytwo percent of PBC had elevated expression of hitrotyrosine in their bile duct epithelial cells (BECs) (P = ,0316). Furthermore, the BEG in PBC also demonstrated apoptotic changes.MPO-positive inflammatory cells were also noted adjacent to the basement membrane. In contrast, the liver of normal subjects showed few apoptotic changes in the bile ducts, with no evidence of MPO staining in the portal area.

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“…12 Viral hepatitis is essentially different from fasting-induced hepatic steatosis since no inflammation was found in liver sections of fasted slc7a3a-null zebrafish mutants, 11 so the regulatory mechanisms of NO signaling under starvation may be entirely distinct from those in pathologic fatty liver disease. Consequently, further investigations are needed to fully uncover the roles of NO signaling in pathological and metabolic syndrome-related NAFLD.…”

Section: Nitric Oxide As a Protector From Nonalcoholic Fatty Liver DImentioning

confidence: 99%

Nitric oxide as a protector from nonalcoholic fatty liver disease

Vinciguerra

2015

Hepatology

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Reply:We appreciate Dr. Bergasa's comment on our findings about the association between cholestatic itch and serum autotaxin (ATX) activity. ATX has phospholipase D activity and generates most of the lysophosphatidic acid (LPA) in blood. LPA is a potent lipidsignaling molecule for which at least six LPA receptors exist, some of which are on neurons. We agree with Dr. Bergasa that the hypothesis of LPA contributing to cholestatic pruritus still needs to be proven. Therefore, we described LPA as a potential pruritogen in cholestatic itch in our review cited above. Although intradermally injected LPA causes scratching, 1 this does not yet prove that LPA produced by ATX is the pruritogen in cholestasis. We are currently testing the hypothesis that ATX and its product, LPA, really do play a role in cholestatic pruritus.Nevertheless, our understanding of the role of ATX in cholestatic pruritus appears more advanced than that of endogenous opioids. In 1992, the group of Dr. Jones has first shown that endogenous opioids are elevated in cholestatic rats. 2 They hypothesized that an increased opioidergic tone in cholestatic patients causes itch. However, a relation between increased opioidergic tone and the extent of pruritus has never been reproducibly demonstrated in cholestatic humans. Dr. Bergasa acknowledges this lack of evidence, but argues that the postulated increased opioidergic tone must be the responsible mechanism because cholestatic patients treated with opioid antagonist often develop an opiate withdrawal-like reaction. However, this does not prove that opioids are the key factor in cholestatic pruritus. Such proof is also not provided by the fact that the opioid antagonist, naloxone, often reduces pruritus in cholestatic patients. Itch signals coming from nerve endings of specific itch fibers are modulated in the spinal cord by interneurons between pain and itch afferents. Pain signals inhibit itch signals through these interneurons. Therefore, opioid antagonists will inhibit pruritus by a general mechanism, irrespective of the causative pruritogen(s). The observation that injection of plasma extracts from cholestatic patients with itch into the medullary dorsal horn of primates causes facial scratching is as much an indication for a role of LPA as for a role of endogenous opioids.A tight correlation exists between serum ATX activity and the extent of itch in cholestasis. 1,3 Thus, also in intrahepatic cholestasis of pregnancy (ICP) we find increased serum ATX activity, compared to healthy pregnant women. In addition, we have shown that several forms of therapy that reduce itch in cholestatic patients also reduce the increased levels of ATX. 3 We are not aware of a comparably elaborate screen for endogenous opioids.We are convinced that ATX is not the only potential pruritogenic factor. 3 Healthy pregnant women (without pruritus) have higher serum ATX levels than cholestatic patients with pruritus. There is a relation between itch and the relative, rather than absolute, increase in serum ATX. Hence Nitri...

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Intrahepatic accumulation of nitrotyrosine in chronic viral hepatitis is associated with histological severity of liver disease

Cited by 101 publications

References 33 publications

Inducible Nitric Oxide Distribution in the Fatty Liver of a Mouse with High Fat Diet-Induced Obesity

Inducible Nitric Oxide Distribution in the Fatty Liver of a Mouse with High Fat Diet-Induced Obesity

Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions

Nitric oxide as a protector from nonalcoholic fatty liver disease

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