Abstract
Ascorbic acid (AA) is recognized as a free radical scavenger that protects cells from oxidative stress-induced damage. However, no studies have investigated the role of AA in acute alcoholic liver disease using senescence marker protein-30 (SMP30) knockout (KO) mice. SMP30 is a novel 34-kDa protein involved in AA biosynthesis. The present study aimed to elucidate the physiological functions of AA in acute ethanol-induced liver injury using SMP30 KO mice, which cannot synthesize AA in vivo. After a 4-week experimental period, mice were divided into six groups. The following three groups comprised the ethanol treatment groups: WT-E group (wild-type), KV-E group (AA-supplemented), and KT-E group (AA-deficient). Mice were exposed to an acute dose of ethanol (6 g ethanol/kg) administered by gavage once a day for three days. The other three control groups, namely, WT-C, KV-C, and KT-C control groups, received an equal volume of water via oral administration. Analysis of changes in body weight showed that mice in the KT-E group had significant loss of body weight compared to the control, KV-E, and WT-E groups. Behavioral analysis revealed that alcohol exposure significantly increased alcohol sensitivity in the KT-E group, whereas the WT-E, KV-E, and control groups developed ethanol tolerance. Aspartate transaminase (AST) levels in the KT-E group were significantly higher than those in the control, KV-E, and WT-E groups. The number of large and binucleated hepatocytes was significantly higher in the KT-E group than in the KV-E and WT-E groups. In addition, cytochrome P450 2E1 (CYP2E1) was over expressed in the central vein in the KT-E group when compared to the KV-E and WT-E groups. Our current findings indicate that AA supplementation in SMP30 KO mice can alleviate alcohol-induced liver damage by down regulating CYP2E1 expression. These results suggest that reduced CYP2E1 expression is a novel mechanism responsible for AA-induced reduction of ethanol-mediated oxidative stress.
Highlights
Ascorbic acid (AA) is widely known as a water-soluble antioxidant that plays a major role in preventing cellular damage caused by free radicals, highly reactive species leading to cell damage and homeostatic disruption [1]
The above findings confirmed that AA deficiency elevates stress levels on whole body system, which in turn leads to greater body weight loss when administered with an equal dose of ethanol compared to normal groups (Figure 1)
Our study showed that the number of binucleated hepatocytes with enlarged nuclei significantly (P < 0.05) increased in the KT-E group (AA-deficient) compared to the KV-E (AA-supplemented) and wild-type group (WT-E) groups (Figure 4)
Summary
Ascorbic acid (AA) is widely known as a water-soluble antioxidant that plays a major role in preventing cellular damage caused by free radicals, highly reactive species leading to cell damage and homeostatic disruption [1]. The antioxidants act at different levels mainly through radical scavenging to detoxify reactive oxygen species (ROS) [2]. A number of reports have suggested that antioxidants, such as vitamin C [3], vitamin E, and selenium, exert inhibiting effects against free radical-induced damage due to alcohol consumption [4] [5]. We described the role of AA in acute alcohol-induced liver injury in senescence marker protein-30 (SMP30) knockout (KO) mice. No similar studies have been conducted using SMP30 KO mice as an animal model for AA deficiency
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