Vanin-1–/– mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores

Abstract

Vanin-1 is a membrane-anchored pantetheinase highly expressed in the gut and liver. It hydrolyzes pantetheine to pantothenic acid (vitamin B5) and the low-molecular-weight thiol cysteamine. The latter is believed to be a key regulating factor of several essential metabolic pathways, acting through sulfhydryl-disulfide exchange reactions between sulfhydryl groups of the enzymes and the oxidized form, cystamine. Its physiological importance remains to be elucidated, however. To explore this point, we developed Vanin-1–deficient mice that lack free cysteamine. We examined the susceptibility of deficient mice to intestinal inflammation, either acute (NSAID administration) or chronic (Schistosoma infection). We found that Vanin-1–/– mice better controlled inflammatory reaction and intestinal injury in both experiments. This protection was associated with increased γ-glutamylcysteine synthetase activity and increased stores of reduced glutathione, as well as reduced inflammatory cell activation in inflamed tissues. Oral administration of cystamine reversed all aspects of the deficient phenotype. These findings suggest that one cysteamine function is to upregulate inflammation. Consequently, the pantetheinase activity of Vanin-1 molecule could be a target for a new anti-inflammatory strategy

Alternative spliced variants in the pantetheinase family of genes expressed in human neutrophils

“…The findings that kidney and liver tissues derived from mouse lacking vanin-1 gene were devoid of pantetheinase activity and tissue cysteamine verified the identity of mouse vanin-1 to an active pantetheinase enzyme in mice (Pitari et al, 2000). Studies using vanin-1-deficient mice demonstrated that cysteamine, a metabolite of pantetheinase, has important roles in inflammation (Berruyer et al, 2006), immune function (Martin et al, 2004;Meghari et al, 2007), and regulation of oxidative stress (Berruyer et al, 2004).…”

The structure of vanin 1: a key enzyme linking metabolic disease and inflammation

“…Vanin 1-deficient mice are not only resistant to gut inflammation but also show increased resistance to stress (Berruyer et al, 2004(Berruyer et al, , 2006Martin et al, 2004;Gensollen et al, 2013). Both vanin 1 and vanin 3 were upregulated (at both the mRNA and the protein levels) by psoriasis-associated proinflammatory cytokines in human keratinocyte cultures (Jansen et al, 2009).…”

“…Both vanin 1 and vanin 3 were upregulated (at both the mRNA and the protein levels) by psoriasis-associated proinflammatory cytokines in human keratinocyte cultures (Jansen et al, 2009). One way in which vanin 1 promotes this inflammatory reaction and intestinal injury is by decreasing the activity of -glutamylcysteine synthetase and thereby decreasing the stores of reduced glutathione (Berruyer et al, 2004;Martin et al, 2004). Additionally, vanin 1 is strongly induced by fasting: Chen and coworkers have shown that it activates gluconeogenesis and increases glucose output in hepatic cells and that this is mediated through the Akt signalling pathway (Chen et al, 2014).…”

Serum Pantetheinase/Vanin Levels Regulate Erythrocyte Homeostasis and Severity of Malaria

“…12 In infectious models, the level of pantetheinase activity (PA) also affects the physiopathological outcome. 10,13 Splenic PA has been shown to contribute to malaria resistance by limiting the level of parasitemia in a Plasmodium chabaudi model of infection. 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 model, cysteamine specifically affected parasite development.…”