TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish<i>s-adenosylhomocysteine hydrolase</i>

Matthews, Randolph P.; Lorent, Kristin; Mañoral-Mobias, Rafael; Huang, Yuehua; Gǒng, Wànkuí; Murray, Ian V.J.; Blair, Ian A.; Pack, Michael

doi:10.1242/dev.027565

Cited by 78 publications

(78 citation statements)

References 81 publications

(103 reference statements)

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“…At present, the evolutionary relationship between these TNF-␣ family members is not resolved (86). A recent study using the zebrafish ducttrip (dtp) mutant phenotype model showed the involvement of zebrafish TNF-␣, but not TNF-␤, in hepatic steatosis and liver degeneration (87). Our results show that both carp TNF-␣ isoforms examined in this study are biologically active.…”

Section: Discussionmentioning

confidence: 57%

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

Forlenza

Magez²,

Scharsack³

et al. 2009

The Journal of Immunology

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Functional characterization of TNF-α in species other than mammalian vertebrates is limited, and TNF-α has been studied in a limited number of fish species, primarily in vitro using recombinant proteins. Studies on TNF-α from different fish species so far pointed to several inconsistencies, in particular with respect to some receptor-mediated activities of fish TNF-α, such as the ability to directly activate phagocytes. In the present study a comprehensive analysis of in vitro as well as in vivo biological activities of two isoforms of carp TNF-α was performed. Our results show that carp TNF-α directly primes carp phagocytes and indirectly promotes typical receptor-mediated activities such as phagocyte activation by acting via endothelial cells. Additionally, for the first time in nonmammalian vertebrate species, the lectin-like activity of fish TNF-α homologs was investigated. Our results show an evolutionary conservation of function of this receptor-independent activity of TNF-α not only in cyprinid fish, but also in perciform and salmonid fish. The role of TNF-α in vivo, during infections of carp with the blood parasite Trypanoplasma borreli, was examined using three fundamentally different but complementary approaches: (1) inhibition of TNF-α expression, (2) overexpression of TNF-α, and (3) inhibition of shedding of membrane-bound TNF-α. Our results show that, also in fish, a tight regulation of TNF-α expression is important, since depletion or excess of TNF-α can make an important difference to survival of infection. Finally, we demonstrate a crucial protective role for membrane-bound TNF-α, which has a yet unexploited function in fish.

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Section: Discussionmentioning

confidence: 57%

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

Forlenza

Magez²,

Scharsack³

et al. 2009

The Journal of Immunology

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“…To further corroborate that reduced methionine content negatively impacts liver development, we examined a previously characterized methionine metabolism disruption: Ahcy functions to break down S-adenosylhomocysteine into adenosine and homocysteine, and ahcy mutant zebrafish display hepatic steatosis and liver degeneration, followed by larval death (Matthews et al, 2009). Morpholino knockdown of ahcy reduces liver size, as reflected in fabp10a expression, at 72 hpf.…”

Section: Methionine Rescues Liver Development Defects In Cnr Mutantsmentioning

confidence: 99%

Cannabinoid receptor signaling regulates liver development and metabolism

et al. 2016

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Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methioninedependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.

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“…S7). Interestingly, treatment of zebrafish with 5-azacytidine, an inhibitor of methylation at hemimethylated cytidine residues, has been shown to globally reduce CpG methylation in larvae by half without increasing tnfa expression (36). Because tnfa levels do not change, there may be a threshold level of demethylation that must be crossed to allow for activation of tnfa.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

168

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

Cited by 78 publications

References 81 publications

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

Cannabinoid receptor signaling regulates liver development and metabolism

Epigenetic control of intestinal barrier function and inflammation in zebrafish

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