ArticleCell death and differentiation2014
Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis.
Article in Cell death and differentiation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 45 citations in OpenAlex.
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- Insulin Resistance in Pediatric Obesity: From Mechanisms to Treatment Strategies.Pediatric diabetes · 2024Review
- ELOVL2 promotes cancer progression by inhibiting cell apoptosis in renal cell carcinoma.Oncology reports · 2022Article
- Integration analysis identifies the role of metallothionein in the progression from hepatic steatosis to steatohepatitis.Frontiers in endocrinology · 2022Article
- New targets for NAFLD.JHEP reports : innovation in hepatology · 2021Review
- Identification of a Metabolic, Transcriptomic, and Molecular Signature of Patatin-Like Phospholipase Domain Containing 3-Mediated Acceleration of Steatohepatitis.Hepatology (Baltimore, Md.) · 2021Article
- Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway.Oxidative medicine and cellular longevity · 2021Article
- Synergistic Induction of Apoptosis by the Combination of an Axl Inhibitor and Auranofin in Human Breast Cancer Cells.Biomolecules & therapeutics · 2020Article
- Review
- Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2019Article
- Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease.Frontiers in endocrinology · 2019Article
- Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy.International journal of molecular sciences · 2018Review
- Hsp90 inhibitor NMS-E973 exerts the anticancer effect against glioblastoma via induction of PUMA-mediated apoptosis.OncoTargets and therapy · 2018Article
- The Transcriptomic Signature Of Disease Development And Progression Of Nonalcoholic Fatty Liver Disease.Scientific reports · 2017Article
- Glycycoumarin inhibits hepatocyte lipoapoptosis through activation of autophagy and inhibition of ER stress/GSK-3-mediated mitochondrial pathway.Scientific reports · 2016Article
- Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis.Journal of lipid research · 2016Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
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(-/-) 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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