More on vitamin C deficiency in mice and humans
Authors: Jin-Kyu Park, Kyu-Shik Jeong
Journal: Hepatology (2011)

We read with great interest Shen's letter and thank him for his interest in our study.1 We agree that the unique compensatory mechanism for adapting to vitamin C deficiency should be considered when the relationship between vitamin C deficiency and liver fibrosis in humans is examined. It has previously been established that senescence marker protein 30 (SMP30) has gluconolactonase activity, which plays a major role in L-ascorbic acid (vitamin C) biosynthesis in the liver.2 Therefore, vitamin C deficiency is induced in SMP30 knockout mice by their inability to synthesize vitamin C; the same is true for L-gulono-γ-lactone oxidase (GLO) knockout mice, humans, primates, guinea pigs, and fruit bats. In our study, we found novel evidence showing that liver fibrosis is ameliorated by vitamin C deficiency through the up-regulated expression of peroxisome proliferator-activated receptor γ (PPAR-γ) in SMP30 knockout mice.1 Because PPAR-γ plays a pivotal role in cellular senescence,3 it is believed that the cellular senescence of liver parenchymal and nonparenchymal cells is the main factor in the amelioration of liver fibrosis due to vitamin C deficiency. Recently, Montel-Hagen etal.4 demonstrated that erythrocyte glucose transporter 1 (Glut1) triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C: the preference of Glut1 is switched from glucose to the oxidized form of vitamin C, L-dehydroascorbic acid (DHA). This means that mammals unable to synthesize vitamin C have a compensatory mechanism for recycling vitamin C. However, in adult mice, erythrocytes do not harbor Glut1 and do not transport DHA, and this means that there is no compensatory mechanism via Glut1 for vitamin C deficiency in mice. Therefore, the condition of complete vitamin C deficiency can be easily induced in SMP30 knockout mice and GLO knockout mice in comparison with human beings and primates. In our study,1 we showed that the serum vitamin C level of the SMP30 knockout mice was almost undetectable, and this indicated that the SMP30 knockout mice did not have another compensatory mechanism for their vitamin C deficiency. Consequently, we concluded that their vitamin C deficiency ameliorated liver fibrosis through the induction of cellular senescence by up-regulated PPAR-γ. When we extend our results with SMP30 knockout mice to human beings, we should point out a few factors with respect to the unique compensatory mechanism for vitamin C deficiency. First, we need to note the process of the formation and degradation of DHA in vivo. Although human erythrocytes can recycle DHA by converting it to ascorbic acid, it is known that mammalian plasma has a system rapidly promoting the hydrolysis of DHA into diketogulonate (DKG), which is rapidly degraded into 5-carbon and 4-carbon species.5 Moreover, previous studies have revealed that the hydrolysis of DHA into DKG is irreversible in vivo.6 These results mean that some DHA can be recycled and that some DHA can be hydrolyzed into DKG. Eventually, if there is no supply of vitamin C, all the DHA may be hydrolyzed into DKG, and this would induce vitamin C deficiency; however, human beings and primates have a unique compensatory mechanism for DHA recycling. Therefore, it is strongly believed that human beings and primates need an appropriate intake of vitamin C. Returning to our study1 and the relationship between vitamin C and liver fibrosis in human beings, we strongly expect that ameliorated liver fibrosis will be observed to cause cellular senescence in human beings with complete vitamin C deficiency, as we have demonstrated in SMP30 knockout mice. However, in comparison with SMP30 knockout mice, inducing the condition of complete vitamin C deficiency might take much longer in human beings and primates because of their compensatory mechanism for adapting to vitamin C deficiency. In future studies on the relationship between the amount of vitamin C intake and liver fibrosis in humans, we totally agree that the unique compensatory mechanism for adapting to vitamin C deficiency should be considered. Jin-Kyu Park Ph.D.*, Kyu-Shik Jeong D.V.M., Ph.D.* , * College of Veterinary Medicine Kyungpook National University Daegu, Republic of Korea, Stem Cell Therapeutic Research Institute Kyungpook National University Daegu, Republic of Korea.