Rdh13 deficiency weakens carbon tetrachloride-induced liver injury by regulating Spot14 and Cyp2e1 expression levels

Abstract

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.

Keywords

retinol dehydrogenase 13 / carbon tetrachloride / acute liver injury / Cyp2e1 / Spot14

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81430028), the Ministry of Science and Technology of China (No. 2011BAI15B02), the grants from the Science and Technology Commission of Shanghai Municipality (Nos.13DZ2280600 and 15DZ2290800), and the grant from Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University (No. 81300776).

Compliance with ethics guidelines

Xiaofang Cui, Benting Ma, Yan Wang, Yan Chen, Chunling Shen, Ying Kuang, Jian Fei, Lungen Lu, and Zhugang Wang declare no conflicts of interests. All institutional and national guidelines for the care and use of laboratory animals were followed.

Electronic Supplementary Material&chsp;Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-017-0568-x and is accessible for authorized users.

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