A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis

Arvelo, Maria B.; Cooper, Jeffrey T.; Longo, Christopher R.; Daniel, Soizic; Grey, Shane T.; Mahiou, Jérôme; Czismadia, Eva; Abu‐Jawdeh, Graziella; Ferran, Christiane

doi:10.1053/jhep.2002.31309

Cited by 135 publications

(138 citation statements)

References 41 publications

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“…A20 protein levels were moderately higher in livers of A20 HET mice at baseline, agreeing with increased activation in these livers of the transcriptional regulator of A20, NF-κB. 9,15,16 A20 HET livers demonstrate heightened intra-hepatic levels of TNF and IL-6 but no increase in hepatocyte apoptosis following PH. PH increases circulating and intrahepatic TNF and IL-6 levels to prime entry of hepatocytes into cell cycle.…”

supporting

confidence: 61%

“…12 Excessive and extended production of TNF and IL-6 in HET livers likely relates to their inability to mount an adequate post-PH surge of NF-κB inhibitory A20, a pre-requisite for secondary containment of these largely NF-κB-dependent cytokines. 13 However, even if reduced, levels of the antiapoptotic A20 9 in HET livers following PH were still sufficient to preclude higher rate of hepatocyte apoptosis. This suggests that other anti-apoptotic mechanisms must compensate for lower A20 levels in protecting hepatocytes post PH.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Our laboratory contributed novel leads to such therapies by exposing the dramatic survival advantage afforded by hepatic overexpression of NF-κB-inhibitory and ubiquitin-editing protein, A20, 7,8 in mouse models of severe toxic or ischemic liver injuries, 9,10 and of extended (78%) and radical (87%) hepatectomy. 4 A20 confers this advantage by (i) limiting inflammation through inhibition of NF-κB activation, (ii) protecting hepatocytes from apoptosis, 9 (iii) reducing oxidative stress by increasing peroxisome proliferator-activated receptoralpha (PPARα) expression, 10 (iv) promoting hepatocyte proliferation by decreasing cyclin-dependent kinase inhibitor (CDKI) p21, enhancing interleukin-6/signal transducer and activator of transcription-3 (IL-6/STAT3) regenerative signals, and (v) optimizing energy production by improving fatty acid (FA) metabolism. 4,11,12 A20 homozygous KO mice are born cachectic, and die within 3-6 weeks of birth from systemic inflammation, predominantly in the liver.…”

mentioning

confidence: 99%

“…Significant upregulation of A20 in humans and mice livers following hepatectomy suggests that A20 is also an active player in the liver's physiologic regenerative response. 1,4,9,12 We explored this hypothesis by evaluating LR following two-third partial hepatectomy (PH) in female A20 heterozygous knockout (HET) mice that show no pathological phenotype at baseline, including in the liver. This procedure is impossible in shortlived cachectic A20 KO mice.…”

mentioning

confidence: 99%

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Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

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supporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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“…A20 is a cytoplasmic seven zinc finger protein that is upregulated by the proinflammatory transcription factor NF-B in most cell types, including hepatocytes. [6][7][8][9] In endothelial cells, A20 has a dual cytoprotective function. It is anti-inflammatory through inhibition of NF-B in a negative feedback loop and is antiapoptotic through inhibition of the caspase cascade at the level of initiator caspase 8.…”

mentioning

confidence: 99%

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Longo¹,

Patel²,

Shrikhande³

et al. 2005

Hepatology

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The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-B. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21 waf1 . In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti-inflammatory, antiapoptotic and pro-proliferative functions, A20-based therapies could be beneficial in prevention and treatment of FHF. (HEPATOLOGY 2005;42:156-164.)

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The E3 ubiquitin ligase MuRF2 attenuates LPS‐induced macrophage activation by inhibiting production of inflammatory cytokines and migration

et al. 2018

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Muscle RING‐finger (MuRF) proteins are E3 ubiquitin ligases that are expressed in striated muscle. MuRF2 is an important member of this family, but whether it is expressed in tissues other than striated muscle has not been thoroughly elucidated to date. In this study, we determined that Mu RF 2 is also expressed in other vital organs, including liver, lung, brain, spleen and kidney. Moreover, we show that the level of Mu RF 2 expression is significantly decreased in hepatic mononuclear cells of mice with lipopolysaccharide ( LPS )/ d ‐galactosamine‐induced hepatitis and negatively correlated with the serum levels of alanine aminotransferase and aspartate aminotransferase in these mice. Furthermore, the expression of Mu RF 2 was down‐regulated in RAW 264.7 cells activated with LPS but not in cells treated with polyinosinic‐polycytidylic acid (Poly(I:C)) or with lipidosome plus Poly(I:C). We also found that Mu RF 2 was able to translocate from the cytoplasm to the nucleus in RAW 264.7 cells activated with LPS but not in cells treated with Poly(I:C). In addition, we demonstrated that interleukin 6 and tumour necrosis factor α production and macrophage migration were inhibited after MuRF2 was overexpressed in RAW 264.7 cells. We further verified that nuclear factor‐κB p65 subunit level was greatly reduced in RAW 264.7 macrophage nuclei by gain of function. Taken together, these findings indicate that Mu RF 2 may rescue LPS ‐induced macrophage activation by suppressing the production of proinflammatory cytokines and cell migration. We also identify a novel function of Mu RF 2 in non‐muscle tissues and cells.

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A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis

Cited by 135 publications

References 41 publications

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

The E3 ubiquitin ligase MuRF2 attenuates LPS‐induced macrophage activation by inhibiting production of inflammatory cytokines and migration

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