Rdh13 deficiency weakens carbon tetrachloride-induced liver injury by regulating Spot14 and Cyp2e1 expression levels
Xiaofang Cui1,2, Benting Ma1, Yan Wang3, Yan Chen1, Chunling Shen1, Ying Kuang2, Jian Fei2, Lungen Lu3(), Zhugang Wang1,2()
1. State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China 2. Shanghai Research Center for Model Organisms, Shanghai 201203, China 3. Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
Mitochondrion-localized retinol dehydrogenase 13 (Rdh13) is a short-chain dehydrogenase/reductase involved in vitamin A metabolism in both humans and mice. We previously generated Rdh13 knockout mice and showed that Rdh13 deficiency causes severe acute retinal light damage. In this study, considering that Rdh13 is highly expressed in mouse liver, we further evaluated the potential effect of Rdh13 on liver injury induced by carbon tetrachloride (CCl4). Although Rdh13 deficiency showed no significant effect on liver histology and physiological functions under regular culture, the Rdh13−/− mice displayed an attenuated response to CCl4-induced liver injury. Their livers also exhibited less histological changes and contained lower levels of liver-related metabolism enzymes compared with the livers of wild-type (WT) mice. Furthermore, the Rdh13−/− mice had Rdh13 deficiency and thus their liver cells were protected from apoptosis, and the quantity of their proliferative cells became lower than that in WT after CCl4 exposure. The ablation of Rdh13 gene decreased the expression levels of thyroid hormone-inducible nuclear protein 14 (Spot14) and cytochrome P450 (Cyp2e1) in the liver, especially after CCl4 treatment for 48 h. These data suggested that the alleviated liver damage induced by CCl4 in Rdh13−/− mice was caused by Cyp2e1 enzymes, which promoted reductive CCl4 metabolism by altering the status of thyroxine metabolism. This result further implicated Rdh13 as a potential drug target in preventing chemically induced liver injury.
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