Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence?

Abstract

L-ergothioneine (ET), a putative antioxidant compound acquired by animals through dietary sources, has been suggested to accumulate in certain cells and tissues in the body that are predisposed to high oxidative stress. In the present study, we identified an elevation of ET in the liver of a guinea pig model of non-alcoholic fatty liver disease (NAFLD), elucidated a possible mechanism for the increased uptake and investigated the possible role for this accumulation. This increase in liver ET levels correlated with cholesterol accumulation and disease severity. We identified an increase in the transcriptional factor, RUNX1, which has been shown to upregulate the expression of the ET-specific transporter OCTN1, and could consequently lead to the observable elevation in ET. An increase was also seen in heat shock protein 70 (HSP70) which seemingly corresponds to ET elevation. No significant increase was observed in oxidative damage markers, F2-isoprostanes, and protein carbonyls, which could possibly be attributed to the increase in liver ET through direct antioxidant action, induction of HSP70, or by chelation of Fe(2+), preventing redox chemistry. The data suggest a novel mechanism by which the guinea pig fatty liver accumulates ET via upregulation of its transporter, as a possible stress response by the damaged liver to further suppress oxidative damage and delay tissue injury. Similar events may happen in other animal models of disease, and researchers should be aware of the possibility.

Ergothioneine – a diet‐derived antioxidant with therapeutic potential

“…Some studies have presented evidence that ET may be accumulated at sites of tissue injury, in particular in fatty liver disease, liver fibrosis, pressure overloaded and infarcted hearts and pre-eclampsia. This accumulation seems to relate to an increased expression of the gene encoding OCTN1, resulting in increased transporter activity [46][47][48][49]. We have suggested [46,50] that this is a deliberate cytoprotective mechanism (Fig.…”

The biology of ergothioneine, an antioxidant nutraceutical

“…ERG has been shown to decrease oxidative stress in the liver and kidney of rats (469) , rescued cells from β-amyloid-induced apoptotic death (231) , protected against palmitic acid-induced cell death (470) , mercuric chloride-induced cellular dysfunction (471) , and prevented Cu-induced oxidative damage to DNA (472,473) . It is protective against the oxidation of various kinds of molecule (251,474) , including astaxanthin (475) , and accumulates in a guinea-pig model of non-alcoholic fatty liver disease (476) , massively so in mouse models of myocardial infarction and heart failure (477) , and in a rat model of optic nerve crush (478) . It serves to resist H 2 O 2 -induced cell death (479) , pyrogallolinduced toxicity (124) , cisplatin- (480) or oxaliplatin-induced (481) toxicity, glucose-induced senescence (246,482) , as well as lipopolysaccharide-induced inflammation (483) .…”

Inhibition of amyloid‐induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model

“…We have also identified the presence of ET in post-mortem human brain and cerebrospinal fluid (unpublished data). Moreover, evidence suggests that that tissues may increase ET uptake (by elevating expression of its transporter, OCTN1) in response to disease or tissue injury, to possibly mitigate further oxidative damage [26,64]. In addition to alleviating Ab oligomer-mediated toxicity as demonstrated in this study, ET has also been demonstrated to function as an antioxidant [23,24], chelate metal ions [58,60], modulate inflammation [65,66], accumulate in mitochondria and protect against mitochondrial dysfunction [67,68] and prevent NMDA excitotoxicity-induced neuronal death in rat retinal neurons [29].…”