In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases

Seki, Shuichi; Kitada, Takuya; Yamada, Takao; Sakaguchi, Hiroki; Nakatani, Kazuki; Wakasa, Kenichi

doi:10.1016/s0168-8278(02)00073-9

Cited by 466 publications

(300 citation statements)

References 38 publications

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“…The importance of oxidative stress in NASH pathogenesis is underscored by recent findings showing the effectiveness of vitamin E in preventing liver injury progression in patients [28]. In our animal model, silibinin was able to decrease both isoprostanes, which are sensitive markers of lipoperoxidation [29], and 8-OHG, a marker of DNA damage, which is increased in NAFLD patients in relation to degree of liver injury [30] and in patients with obesity/diabetes cardiomyopathy [17]. The used dose is higher than in the commercially available oral formulations of silymarin/silibinin, but the safety for comparable dosage of silibinin has been showed both in healthy volunteers [31] and in patients with chronic liver disease [32,33].…”

Section: Discussionmentioning

confidence: 54%

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Salamone¹,

Galvano²,

Marino³

et al. 2012

Digestive and Liver Disease

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a b s t r a c tBackground: Nonalcoholic fatty liver disease is a chronic metabolic disorder with significant impact on cardiovascular and liver mortality. Aims: In this study, we examined the effects of silibinin on liver and myocardium injury in an experimental model of nonalcoholic fatty liver disease. Methods: A four-week daily dose of silibinin (20 mg/kg i.p.) was administrated to db/db mice fed a methionine-choline deficient diet. Hepatic and myocardial histology, oxidative stress and inflammatory cytokines were evaluated. Results: Silibinin administration decreased HOMA-IR, serum ALT and markedly improved hepatic and myocardial damage. Silibinin reduced isoprostanes, 8-deoxyguanosine and nitrites/nitrates in the liver and in the heart of db/db fed the methionine-choline deficient diet, whereas glutathione levels were restored to lean mice levels in both tissues. Consistently, liver mitochondrial respiratory chain activity was significantly impaired in untreated mice and was completely restored in silibinin-treated animals. TNF-␣ was increased whereas IL-6 was decreased both in the liver and heart of db/db fed methionine-choline deficient diet. Silibinin reversed heart TNF-␣ and IL-6 expression to control mice levels. Indeed, liver JNK phosphorylation was reduced to control levels in treated animals. Conclusions: This study demonstrates a combined effectiveness of silibinin on improving liver and myocardial injury in experimental nonalcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 54%

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Salamone¹,

Galvano²,

Marino³

et al. 2012

Digestive and Liver Disease

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“…Mitochondria have been shown to play a major role in the development of oxidative stress in NAFLD through an increased production of ROS (106,119). Mitochondria function in the catabolic processing of carbohydrates and fatty acids, through processing glycolysis end products and b-oxidation, to produce nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH 2 ) as input for the ETC.…”

Section: Mitochondria In Nafldmentioning

confidence: 99%

Mitochondrial Morphology in Metabolic Diseases

Galloway

Yoon

2013

Antioxidants & Redox Signaling

112

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Significance: Mitochondria are the cellular energy-producing organelles and are at the crossroad of determining cell life and death. As such, the function of mitochondria has been intensely studied in metabolic disorders, including diabetes and associated maladies commonly grouped under all-inclusive pathological condition of metabolic syndrome. More recently, the altered metabolic profiles and function of mitochondria in these ailments have been correlated with their aberrant morphologies. This review describes an overview of mitochondrial fission and fusion machineries, and discusses implications of mitochondrial morphology and function in these metabolic maladies. Recent Advances: Mitochondria undergo frequent morphological changes, altering the mitochondrial network organization in response to environmental cues, termed mitochondrial dynamics. Mitochondrial fission and fusion mediate morphological plasticity of mitochondria and are controlled by membrane-remodeling mechanochemical enzymes and accessory proteins. Growing evidence suggests that mitochondrial dynamics play an important role in diabetes establishment and progression as well as associated ailments, including, but not limited to, metabolism-secretion coupling in the pancreas, nonalcoholic fatty liver disease progression, and diabetic cardiomyopathy. Critical Issues: While mitochondrial dynamics are intimately associated with mitochondrial bioenergetics, their cause-and-effect correlation remains undefined in metabolic diseases. Future Directions: The involvement of mitochondrial dynamics in metabolic diseases is in its relatively early stages. Elucidating the role of mitochondrial dynamics in pathological metabolic conditions will aid in defining the intricate form-function correlation of mitochondria in metabolic pathologies and should provide not only important clues to metabolic disease progression, but also new therapeutic targets. Antioxid. Redox Signal. 19,[415][416][417][418][419][420][421][422][423][424][425][426][427][428][429][430]

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“…Histological studies of biopsies taken from patients with NAFLD indicate that a significant number of patients progress to is exceeded. Oxidative stress, mitochondrial dysfunction and upregulation of pro-inflammatory cytokines ("second hits") have been suggested to be major consequences of cellular lipid overload [7][8][9], potentially contributing to inflammatory liver damage and fibrogenesis in NASH.…”

Section: Introductionmentioning

confidence: 99%

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

et al. 2009

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Abbreviations: CM (conditioned medium); FFAs (free fatty acids); HSC (hepatic stellate cells); NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); MMP (matrix-metallo-proteinase); NFκB (nuclear-factor κB); PHH (primary human hepatocytes); TIMP-1/-2 (tissue inhibitor of metallo-proteinase-1/-2) Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells (HSCs), the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media (CM) from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 (TIMP-1), TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.

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In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases

Cited by 466 publications

References 38 publications

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Mitochondrial Morphology in Metabolic Diseases

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

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