Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis

Feldstein, Ariel E.; Canbay, Ali; Angulo, Paul; Taniai, Makiko; Burgart, Lawrence J.; Lindor, Keith D.; Gores, Gregory J.

doi:10.1016/s0016-5085(03)00907-7

Cited by 975 publications

(811 citation statements)

References 24 publications

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“…(also known as TRAIL-R2), TNFR1) are up-regulated on hepatocytes in the setting of steatosis; death receptor activation has been implicated as an important stimulus to hepatocyte apoptosis and necroptosis in NASH [55][56][57][58] . Whether hedgehog stimulates fibrosis through direct effects on stellate cells or indirect effects on fatty liver injury is currently under study 75 .…”

Section: [H2] Children and Adolescentsmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease

Rinella

2015

JAMA

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1,621

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Section: [H2] Children and Adolescentsmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease

Rinella

2015

JAMA

2,000

1,621

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“…In NAFLD patients, a positive correlation exists between hepatocyte apoptosis, hepatic inflammation, and fibrosis. 30 Increasing steatosis in patients with CHC correlates with enhanced hepatocyte apoptosis and increased stage of fibrosis. 24 This finding is supported by evidence that hepatic steatosis in patients with CHC is associated with hepatic inflammation and advanced stages of fibrosis.…”

Section: Increased Fibrosismentioning

confidence: 99%

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Harrison

2005

Clinical Gastroenterology and Hepatology

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“…2 NASH is associated with hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte apoptosis. 3,4 An excess of FFA is particularly deleterious for the liver, as saturated FFA injure hepatocytes by inducing apoptosis, a phenomenon known as lipotoxicity. 5,6 The importance of liver apoptosis in NAFLD pathogenesis is highlighted by the observation that hepatocyte lipoapoptosis is increased in correlation with disease severity.…”

mentioning

confidence: 99%

“…5,6 The importance of liver apoptosis in NAFLD pathogenesis is highlighted by the observation that hepatocyte lipoapoptosis is increased in correlation with disease severity. 3 Thus, unravelling the cellular and molecular mechanisms promoting liver injury during NAFLD pathogenesis is of biomedical importance and human health relevance.…”

mentioning

confidence: 99%

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

et al. 2014

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Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro-apoptotic BH3-only proteins Bim and PUMA. Kelch-like ECH-associated protein (Keap)-1 is a BTB/Kelch protein that can regulate the expression of Bcl-2 protein and control apoptotic cell death. Yet, the role of Keap1 in hepatocyte lipotoxicity is unclear. Here we demonstrate that Keap1 protein was rapidly degraded in hepatocytes, through autophagy in a p62-dependent manner, in response to the toxic saturated FFA palmitate, but not following incubation with the non-toxic FFA oleic acid. Stable knockdown of Keap1 expression, using shRNA technology, in hepatocarcinoma cell lines induced spontaneous cell toxicity that was associated with JNK1-dependent upregulation of Bim and PUMA protein levels. Also, Keap1 knockdown further sensitized hepatocytes to lipoapoptosis by palmitate. Likewise, primary hepatocytes isolated from liver-specific Keap1 À / À mice displayed higher Bim and PUMA protein levels and demonstrated increased sensitivity to palmitate-induced apoptosis than wild-type mouse hepatocytes. Finally, stable knockdown of Bim or PUMA expression prevented cell toxicity induced by loss of Keap1. These results implicate p62-dependent autophagic degradation of Keap1 by palmitate as a mechanism contributing to hepatocyte lipoapoptosis.

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Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis

Cited by 975 publications

References 24 publications

Nonalcoholic Fatty Liver Disease

Nonalcoholic Fatty Liver Disease

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

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