Title:Influence of Vanin-1 and Catalytic Products in Liver During Normal and Oxidative Stress Conditions
Volume: 22
Issue: 20
Author(s): Daniel W. Ferreira, Philippe Naquet and Jose E. Manautou
Affiliation:
Keywords:
Vanin, liver, mitochondria, oxidative stress, cysteamine, cystamine, hepatoxicity, pantetheinase, coenzyme A.
Abstract: In liver, cysteamine in all probability represents a “low-capacity, high-affinity” scavenger
of ROS. The available body of evidence suggests that reduced cysteamine and oxidized cystamine exist
in equilibrium and that this ratio acts as an active redox sensor within the cell much like GSH. During
normal liver homeostasis cysteamine’s antioxidant properties are evident. Highly metabolic and/or
pro-oxidative conditions, such as in mice treated with peroxisome proliferators, shift this equilibrium
to favor the oxidized form. Under these conditions, cystamine is likely able to inactivate proteins involved in energy biogenesis
through cysteaminylation of critical Cys residues as has been shown in vitro. This would allow cystamine to function
as a “metabolic brake” to prevent the formation of additional ROS. In vivo, subcellular localization, pH, reducing capacity,
FMO status and metabolic rate are all probable factors in determining the cysteamine:cystamine ratio. The availability
of free cysteamine is also regulated by hydrolysis of pantetheine by pantetheinase. This cleavage results in the formation
of pantothenic acid, a precursor to Coenzyme A which is prominently involved with lipid metabolism and energy
production by the β -oxidation pathway and TCA cycle, respectively. Expression of pantetheinase is controlled by the
Vnn1 gene and is upregulated in response to free fatty acids, PPAR activation or oxidative stress. The use of Vnn1 knockout
mice has provided clear evidence that Vnn1 modulates redox and immune pathways In vivo, both of which appear at
least partially due to a loss of cysteamine/cystamine. Immunologically, Vnn1 expression may influence cell signaling indirectly
through maintenance of disulfide bonds or directly by interaction of pantetheinase on the cell surface. Cysteamine
treatment has been used clinically as an antidote to APAP poisoning and in animal models against hepatotoxicants including
APAP, galactosamine and CCl4. Protection in animal models occurs even when administered up to 12 hours following
intoxication, suggesting that protection is the result of effects that occur downstream of bioactivation and covalent binding
of reactive metabolites to target cellular macromolecules. Currently, the downstream influences of Vnn1 expression and
cysteamine at endogenous concentrations remain largely unknown. Vnn1 knockout mice represent a valuable tool available
to researchers investigating these events. Future studies in the field are needed to elucidate the precise mechanisms
by which pantetheinase and/or cysteamine impact immune cell recruitment, cell signaling and survival, though it is clear
that these factors have far reaching implications in the fields of immunology and toxicology.
