A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

Damrauer, Scott M.; Studer, Peter; Silva, Cleide G. da; Longo, Christopher R.; Ramsey, Haley E.; Csizmadia, Eva; Shrikhande, Gautam; Scali, Salvatore T.; Libermann, Towia A.; Bhasin, Manoj; Ferran, Christiane

doi:10.1371/journal.pone.0017715

Cited by 33 publications

(30 citation statements)

References 71 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36 However, excessive levels of IL-6 following PH halt hepatocyte proliferation 17 by increasing p21 transcription to block Cyclin/CDK complexes 37 and by binding STAT3 to inhibit its pro-regenerative signals. 38 Having reported that A20 overexpression decreases p21 mRNA and protein levels, 4,11,12 we were intrigued by the comparable levels of p21 mRNA in HET and WT livers post PH. This suggested that A20 was either not a physiologic regulator of p21 mRNA, or that homozygous (not heterozygous) KO of A20 (paralleled by even higher IL-6 levels) was required to increase p21 mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

“…These results agree with lipid metabolism being the most affected GO category in A20 gain-of-function studies. 11 We validated differential expression of key pre-PH genes by qPCR and demonstrated significantly higher DBP and RGS16 and lower PDK4 mRNA levels in HET versus WT livers (Figure 4b). However, there was only a trend towards lower Figure 3 A20 HET negatively modulates hepatic expression of cell cycle regulators before and after PH.…”

mentioning

confidence: 80%

“…4,11 We expected the reverse in HET livers, yet baseline and PH-induced upregulation of p21 mRNA was comparable in HET and WT livers (Figure 3c). However, by immunohistochemistry, the number of p21 + hepatocytes/high power field was significantly higher in HET versus WT livers 2 d post PH (Figure 3d), with a trend towards higher number at baseline.…”

mentioning

confidence: 82%

“…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. 13 This highlights A20's prominence in the liver's physiologic anti-inflammatory and anti-apoptotic defense mechanisms.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 80%

mentioning

confidence: 82%

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…A20 prevents transplant vasculopathy by inhibiting endothelial cells (EC) activation and therefore decreasing leukocyte recruitment, by suppressing EC apoptosis and by inhibiting smooth muscle cell (SMC) proliferation (1)(2)(3)(4)(5)(6)(7). Previous studies revealed that accommodated xenografts or allografts that resist chronic rejection express elevated levels of endogenous A20 in the graft vasculature (1,7).…”

mentioning

confidence: 99%

A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes

et al. 2015

Self Cite

View full text Add to dashboard Cite

A20 protects against pathologic vascular remodeling by inhibiting the inflammatory transcription factor NF-kB. A20's function has been attributed to ubiquitin editing of receptor-interacting protein 1 (RIP1) to influence activity/stability. The validity of this mechanism was tested using a murine model of transplant vasculopathy and human cells. Mouse C57BL/6 aortae transduced with adenoviruses containing A20 (or b-galactosidase as a control) were allografted into major histocompatibility complex-mismatched BALB/c mice. Primary endothelial cells, smooth muscle cells, or transformed epithelial cells (all human) were transfected with wild-type A20 or with catalytically inactive mutants as a control. NF-kB activity and intracellular localization of RIP1 was monitored by reporter gene assay, immunofluorescent staining, and Western blotting. Native and catalytically inactive versions of A20 had similar inhibitory effects on NF-kB activity (270% vs. 276%; P > 0.05). A20 promoted localization of RIP1 to insoluble aggresomes in murine vascular allografts and in human cells (53% vs. 0%) without altering RIP1 expression, and this process was increased by the assembly of polyubiquitin chains (87% vs. 28%; P < 0.05). A20 captures polyubiquitinated signaling intermediaries in insoluble aggresomes, thus reducing their bioavailability for downstream NF-kB signaling. This novel mechanism contributes to protection from vasculopathy in transplanted organs treated with exogenous A20.-Enesa, K., Moll, H. P., Luong, L., Ferran, C., Evans, P. C. A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes.

show abstract

Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache

Perry

Blake

Buettner

et al. 2016

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

Objective Chronic migraine (CM) is often associated with chronic tenderness of pericranial muscles. In fact, a distinct increase in muscle tenderness prior to onset of occipital headache that eventually progresses into a full blown migraine attack is common. This experience raises the possibility that some CM attacks originate outside the cranium. The objective of this study was to determine whether there are extracranial pathophysiologies in these headaches. Methods We biopsied and measured the expression of gene transcripts (mRNA) encoding proteins that play roles in immune and inflammatory responses in affected (i.e., where the head hurts) calvarial periosteum of (a) patients whose CMs are associated with muscle tenderness and (b) patients with no history of headache. Results Expression of proinflammatory genes (e.g., CCL8, TLR2) in the calvarial periosteum significantly increases in CM patients attesting to muscle tenderness, whereas expression of genes that suppress inflammation and immune cell differentiation (e.g., IL10RA, CSF1R) decreased. Interpretation Because the up-regulated genes were linked to activation of white blood cells, production of cytokines, and inhibition of NFKB, and the down-regulated genes linked to prevention of macrophage activation and cell lysis, we suggest that the molecular environment surrounding periosteal pain fibers is inflamed and in turn activates trigeminovascular nociceptors that reach the affected periosteum through suture branches of intracranial meningeal nociceptors and/or somatic branches of the occipital nerve. This study provides the first set of evidence for localized extracranial pathophysiology in chronic migraine.

show abstract

A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

Cited by 33 publications

References 71 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 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes

Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache

Contact Info

Product

Resources

About