Hepatocyte Apoptosis, Expression of Death Receptors, and Activation of NF-κB in the Liver of Nonalcoholic and Alcoholic Steatohepatitis Patients

Ribeiro, Paulo S.; Cortez‐Pinto, Helena; Solá, Susana; Castro, Rui E.; Ramalho, Rita M.; Baptista, António M.; Moura, Miguel Carneiro de; Camilo, M.; Rodrigues, Cecília M. P.

doi:10.1111/j.1572-0241.2004.40009.x

Cited by 357 publications

(247 citation statements)

References 44 publications

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“…JNK contributes to insulin resistance via direct phosphorylation and degradation of IRS1, dampening the intracellular signalling pathway downstream of the insulin receptor [52]. NF-κB activation has been demonstrated in the liver of patients with NASH [55], and leads to increased transcription of numerous proinflammatory genes that amplify the response [52]. In the presence of systemic inflammation, the liver is again both the target of and contributor to inflammatory changes.…”

Section: Biological Mechanisms Potentially Responsible For Acceleratementioning

confidence: 99%

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

2008

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Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher (∼70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

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Section: Biological Mechanisms Potentially Responsible For Acceleratementioning

confidence: 99%

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

2008

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“…Interestingly, cell death by apoptosis may also constitute an important component of disease progression [4]. In fact, members of our team and others have already demonstrated that hepatocyte apoptosis is a prominent pathological feature in patients with NASH and NAFLD [5,6]. Nevertheless, the exact mechanisms of hepatocyte apoptosis in NASH and underlying factors of NAFLD progression and pathogenesis remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

et al. 2011

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Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and characterised by different degrees of hepatic lesion. Its pathogenesis and correlation with apoptosis and insulin resistance in insulin target tissues remains incompletely understood. We investigated how insulin signalling, caspase activation and apoptosis correlate with different NAFLD stages in liver, muscle and visceral adipose tissues. Methods Liver, muscle and adipose tissue biopsies from 26 morbidly obese patients undergoing bariatric surgery were grouped according to the Kleiner-Brunt scoring system into simple steatosis, and less severe and more severe nonalcoholic steatohepatitis (NASH). Apoptosis was assessed by DNA fragmentation, and caspase-2 and -3 activation. Insulin signalling and c-Jun NH 2 -terminal kinase (JNK) proteins were evaluated by western blot. Results Caspase-3 and -2 activation, and DNA fragmentation were markedly increased in the liver of patients with severe NASH vs in that of those with simple steatosis (p<0.01). Muscle tissue, and to a lesser extent the liver, had decreased tyrosine phosphorylated insulin receptor and insulin receptor substrate in patients with severe NASH, compared with those with simple steatosis (p < 0.01 muscle; p < 0.05 liver). Concomitantly, Akt phosphorylation decreased in muscle, liver and visceral adipose tissues in patients with severe NASH (at least p< 0.05). Finally, JNK phosphorylation was significantly increased in muscle (p< 0.01) and liver (p<0.05) from NASH patients, compared with tissue from those with simple steatosis. Conclusions/interpretation Our results demonstrate a link between apoptosis, insulin resistance and different NAFLD stages, where JNK and caspase-2 may play a key regulatory role.

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“…However, at least 1 report has revealed remarkably elevated hepatic NF-B activity in alcoholic liver disease, which correlates with the degree of inflammation and fibrosis. 9 Injury-induced activation of hepatic NF-B is observed in a variety of nonparenchymal and parenchymal liver cells, indicating that NF-B plays a central role in coordinating the inflammatory and wound healing response by stimulating gene transcription in multiple key cellular players. Kupffer cells (the liver's resident macrophages) display powerful NF-B activation in response to liver injury by alcohol, carbon tetrachloride, endotoxin, and cholestasis, resulting in production and secretion of proinflammatory cytokines (including the hepatomitogens TNF-␣ and IL-6) that are strongly implicated as promoters of fibrosis and HCC.…”

Section: The Inflammation-fibrosis-cancer Axismentioning

confidence: 99%

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

2007

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Nuclear factor-B (NF-B) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-B in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-B activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma-a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-B signaling system, which should provide a rich source of new therapeutic targets. (HEPATOLOGY 2007;46:590-597.)

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Hepatocyte Apoptosis, Expression of Death Receptors, and Activation of NF-κB in the Liver of Nonalcoholic and Alcoholic Steatohepatitis Patients

Cited by 357 publications

References 44 publications

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

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