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

ABSTRACT: 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 (>40%) 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 >1000 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 pro-regenerative therapies.

SUBMITTER: Studer P

PROVIDER: S-EPMC4816110 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Studer P P da Silva C G CG Revuelta Cervantes J M JM Mele A A Csizmadia E E Siracuse J J JJ Damrauer S M SM Peterson C R CR Candinas D D Stroka D M DM Ma A A Bhasin M M Ferran C C

Cell death and differentiation 20150515 12

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 follow ...[more]

PMID: 25976305

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Project description:BackgroundLiver regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice.Methodology and principal findingsWe performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV.ConclusionThis Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients' outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation.

Project description:Background & aimsLiver resection (LR) in patients with hepatocellular carcinoma (HCC) and clinically significant portal hypertension (CSPH) defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg is not encouraged. Here, we reappraised the outcomes of patients with cirrhosis and CSPH who underwent LR for HCC in highly specialised liver centres.MethodsThis was a retrospective multicentre study from 1999 to 2019. Predictors for postoperative liver decompensation and textbook outcomes were identified.ResultsIn total, 79 patients with a median age of 65 years were included. The Child-Pugh grade was A in 99% of patients, and the median model for end-stage liver disease (MELD) score was 8. The median HVPG was 12 mmHg. Major hepatectomies and laparoscopies were performed in 28% and 34% of patients, respectively. Ninety-day mortality and severe morbidity rates were 6% and 27%, respectively. Postoperative and persistent liver decompensation occurred in 35% and 10% of patients at 3 months. Predictors of liver decompensation included increased preoperative HVPG (p = 0.004), increased serum total bilirubin (p = 0.02), and open approach (p = 0.03). Of the patients, 34% achieved a textbook outcome, of which the laparoscopic approach was the sole predictor (p = 0.004). The 5-year overall survival and recurrence-free survival rates were 55% and 43%, respectively.ConclusionsPatients with cirrhosis, HCC and HVPG ≥10 mmHg can undergo LR with acceptable mortality, morbidity, and liver decompensation rates. The laparoscopic approach was the sole predictor of a textbook outcome.Lay summaryPatients with cirrhosis, hepatocellular carcinoma, and clinically significant portal hypertension (defined as a hepatic venous pressure gradient ≥10 mmHg) can undergo resection with acceptable mortality, morbidity, liver decompensation rates, and a textbook outcome. These results can be achieved in selected patients with preserved liver function, good general status, and sufficient remnant liver volume.

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

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

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