Molecular mechanisms of hepatic apoptosis

Wang, Kewei

doi:10.1038/cddis.2013.499

Cited by 264 publications

(207 citation statements)

References 135 publications

(145 reference statements)

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“…25,26 Studies in knockout mice lacking NF-kB signalling components revealed an essential role of NF-kB in protecting the fetal liver from TNF-induced cell death. 21,22 We therefore hypothesized that the spontaneous apoptosis of NEMO-deficient hepatocytes that results in chronic hepatitis and HCC development in NEMO LPC-KO mice is driven by death receptor signalling.…”

Section: Discussionmentioning

confidence: 99%

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKc, a subunit of the IjB kinase (IKK) complex that is essential for the activation of canonical NF-jB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO LPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO LPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMO LPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMOdeficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO LPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO LPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO LPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.

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Section: Discussionmentioning

confidence: 99%

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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“…Healthy subjects had no history or clinical evidence of previous or present illness. All patients in the ACLF group were managed according to the standard of care, including intensive care monitoring, high-calorie diet (35)(36)(37)(38)(39)(40) cal/kg/day), intravenous albumin, broad-spectrum antibiotics, pentoxifylline for alcoholic hepatitis, antivirals, which included tenofovir for hepatitis B virus (HBV) reactivation, terlipressin for hepatorenal syndrome, and lactulose bowel enemas. In the presence of acute kidney injury, the dose of tenofovir was modified according to creatinine clearance.…”

Section: Methodsmentioning

confidence: 99%

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

et al. 2015

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Acute-on-chronic liver failure (ACLF) is an ailment with high incidence of multiorgan failure (MOF) and consequent mortality. Dysregulated iron homeostasis and macrophage dysfunction are linked to increased incidence of MOF. We investigated whether a panel of circulating iron-regulating proteins are associated with development of MOF and can predict 15-or 30-day mortality in ACLF patients. One hundred twenty patients with ACLF, 20 patients with compensated cirrhosis, and 20 healthy controls were studied. Relative protein expression profiling was performed in the derivative cohort and confirmed in the validation cohort. A panel of iron regulators and indices were determined. Multiparametric flow cytometry for quantitation of labile iron pool (LIP) was performed. Validation studies confirmed lower serum transferrin (Tf) and ceruloplasmin levels in ACLF and ACLF-MOF, compared to patients with cirrhosis and controls (P < 0.01). Serum iron and ferritin levels were markedly elevated (P < 0.001; P < 0.05) and hepcidin levels were lower (P < 0.001) in ACLF patients with MOF than those without and other groups (P < 0.001). Percentage Tf saturation (%SAT) was higher in ACLF-MOF (39.2%; P < 0.001) and correlated with poor outcome (hazard ratio: 6.970; P < 0.01). Intracellular LIP indices were significantly elevated in the subsets of circulating macrophages in ACLF-MOF, compared to other groups (P < 0.01). Whereas expression of iron-regulatory genes was markedly down-regulated, genes related to endoplasmic reticulum stress, apoptosis, and inflammation were up-regulated in ACLF patients, compared to patients with cirrhosis. Severe dysregulation of autophagy mechanisms was also observed in the former. Conclusions: Iron metabolism and transport are severely deranged in ACLF patients and more so in those with MOF. %SAT, circulating hepcidin, and LIP in macrophages correlate with disease severity and %SAT could be used for early prognostication in ACLF patients. (HEPATOLOGY 2015;61:1306-1320

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“…24 We found that at 24 hr after treatment, apoptotic cells decreased (2-fold) in the hucMSC-Ex group compared with the PBS and HFL-Ex groups (Figure 4A; n = 3; *p < 0.05, **p < 0.01). Hoechst 33342 staining revealed fewer apoptotic cells (half-moon nuclei) in the hucMSC-Ex group compared with the PBS and HFL-Ex groups ( Figure 4B; n = 3; *p < 0.05, **p < 0.01).…”

Section: Hucmsc-ex Inhibited Oxidative Stress-induced Apoptosismentioning

confidence: 84%

“…24 Thus, we measured changes in mitochondrial membrane potential in L02 cells treated with or without hucMSC-Ex using JC-1 staining. More cells were fluorescent green in the PBS and HFL-Ex groups, but more cells were fluorescent red in the hucMSC-Ex group (Figure 4Ci).…”

Section: Hucmsc-ex Inhibited Oxidative Stress-induced Apoptosismentioning

confidence: 99%

hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury

et al. 2017

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Exosomes are small biological membrane vesicles secreted by various cells, including mesenchymal stem cells (MSCs). We previously reported that MSC-derived exosomes (MSC-Ex) can elicit hepatoprotective effects against toxicant-induced injury. However, the success of MSC-Ex-based therapy for treatment of liver diseases and the underlying mechanisms have not been well characterized. We used human umbilical cord MSC-derived exosome (hucMSC-Ex) administrated by tail vein or oral gavage at different doses and, in engrafted liver mouse models, noted antioxidant and anti-apoptotic effects and rescue from liver failure. A single systemic administration of hucMSC-Ex (16 mg/kg) effectively rescued the recipient mice from carbon tetrachloride (CCl 4 )-induced liver failure. Moreover, hucMSC-Ex-derived glutathione peroxidase1 (GPX1), which detoxifies CCl 4 and H 2 O 2 , reduced oxidative stress and apoptosis. Knockdown of GPX1 in hucMSCs abrogated antioxidant and anti-apoptotic abilities of hucMSC-Ex and diminished the hepatoprotective effects of hucMSC-Ex in vitro and in vivo. Thus, hucMSC-Ex promote the recovery of hepatic oxidant injury through the delivery of GPX1.

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Molecular mechanisms of hepatic apoptosis

Cited by 264 publications

References 135 publications

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury

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