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

References

[1] Belyaeva OV, Korkina OV, Stetsenko AV, Kedishvili NY. Human retinol dehydrogenase 13 (RDH13) is a mitochondrial short-chain dehydrogenase/reductase with a retinaldehyde reductase activity. FEBS J 2008; 275(1): 138–147

[2] Kavanagh KL, Jörnvall H, Persson B, Oppermann U. Medium- and short-chain dehydrogenase/reductase gene and protein families: the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Cell Mol Life Sci 2008; 65(24): 3895–3906

[3] Oppermann U, Filling C, Hult M, Shafqat N, Wu X, Lindh M, Shafqat J, Nordling E, Kallberg Y, Persson B, Jörnvall H. Short-chain dehydrogenases/reductases (SDR): the 2002 update. Chem Biol Interact 2003; 143-144: 247–253

[4] Jörnvall H, Persson B, Krook M, Atrian S, Gonzàlez-Duarte R, Jeffery J, Ghosh D. Short-chain dehydrogenases/reductases (SDR). Biochemistry 1995; 34(18): 6003–6013

[5] Kramm A, Kisiela M, Schulz R, Maser E. Short-chain dehydrogenases/reductases in cyanobacteria. FEBS J 2012; 279(6): 1030–1043

[6] Simon A, Hellman U, Wernstedt C, Eriksson U. The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases. J Biol Chem 1995; 270(3): 1107–1112

[7] Driessen CA, Janssen BP, Winkens HJ, van Vugt AH, de Leeuw TL, Janssen JJ. Cloning and expression of a cDNA encoding bovine retinal pigment epithelial 11-cis retinol dehydrogenase. Invest Ophthalmol Vis Sci 1995; 36(10): 1988–1996

[8] Haeseleer F, Jang GF, Imanishi Y, Driessen CAGG, Matsumura M, Nelson PS, Palczewski K. Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina. J Biol Chem 2002; 277(47): 45537–45546

[9] Wang H, Cui X, Gu Q, Chen Y, Zhou J, Kuang Y, Wang Z, Xu X. Retinol dehydrogenase 13 protects the mouse retina from acute light damage. Mol Vis 2012; 18: 1021–1030

[10] Kuniyoshi K, Sakuramoto H, Yoshitake K, Abe K, Ikeo K, Furuno M, Tsunoda K, Kusaka S, Shimomura Y, Iwata T. Longitudinal clinical course of three Japanese patients with Leber congenital amaurosis/early-onset retinal dystrophy with RDH12 mutation. Doc Ophthalmol 2014; 128(3): 219–228

[11] Kovalovich K, DeAngelis RA, Li W, Furth EE, Ciliberto G, Taub R. Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice. Hepatology 2000; 31(1): 149–159

[12] Otsuka T, Takagi H, Horiguchi N, Toyoda M, Sato K, Takayama H, Mori M. CCl₄-induced acute liver injury in mice is inhibited by hepatocyte growth factor overexpression but stimulated by NK2 overexpression. FEBS Lett 2002; 532(3): 391–395

[13] Yu C, Wang F, Jin C, Wu X, Chan WK, McKeehan WL. Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice. Am J Pathol 2002; 161(6): 2003–2010

[14] Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA 2004; 101(13): 4477–4482

[15] Yamada Y, Fausto N. Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor. Am J Pathol 1998; 152(6): 1577–1589

[16] Bisht S, Khan MA, Bekhit M, Bai H, Cornish T, Mizuma M, Rudek MA, Zhao M, Maitra A, Ray B, Lahiri D, Maitra A, Anders RA. A polymeric nanoparticle formulation of curcumin (NanoCurc™) ameliorates CCl₄-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest 2011; 91(9): 1383–1395

[17] Zhang F, Shu R, Wu X, Zhao X, Feng D, Wang L, Lu S, Liu Q, Xiang Y, Fei J, Huang L, Wang Z. Delayed liver injury and impaired hepatocyte proliferation after carbon tetrachloride exposure in BPOZ2-deficient mice. Toxicol Lett 2009; 188(3): 201–207

[18] Natsume M, Tsuji H, Harada A, Akiyama M, Yano T, Ishikura H, Nakanishi I, Matsushima K, Kaneko S, Mukaida N. Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice. J Leukoc Biol 1999, 66: 601–608

[19] Bansal MB, Kovalovich K, Gupta R, Li W, Agarwal A, Radbill B, Alvarez CE, Safadi R, Fiel MI, Friedman SL, Taub RA. Interleukin-6 protects hepatocytes from CCl₄-mediated necrosis and apoptosis in mice by reducing MMP-2 expression. J Hepatol 2005; 42(4): 548–556

[20] Gomez-Sanchez EP, Ganjam V, Chen YJ, Liu Y, Clark SA, Gomez-Sanchez CE. The 11β hydroxysteroid dehydrogenase 2 exists as an inactive dimer. Steroids 2001; 66(11): 845–848

[21] Belyaeva OV, Kedishvili NY. Human pancreas protein 2 (PAN2) has a retinal reductase activity and is ubiquitously expressed in human tissues. FEBS Lett 2002; 531(3): 489–493

[22] Kim TS, Maeda A, Maeda T, Heinlein C, Kedishvili N, Palczewski K, Nelson PS. Delayed dark adaptation in 11-cis-retinol dehydrogenase-deficient mice: a role of RDH11 in visual processes in vivo. J Biol Chem 2005; 280(10): 8694–8704

[23] Iannaccone A, Tedesco SA, Gallaher KT, Yamamoto H, Charles S, Dryja TP. Fundus albipunctatus in a 6-year old girl due to compound heterozygous mutations in the RDH5 gene. Doc Ophthalmol 2007; 115(2): 111–116

[24] Ajmal M, Khan MI, Neveling K, Khan YM, Ali SH, Ahmed W, Iqbal MS, Azam M, den Hollander AI, Collin RW, Qamar R, Cremers FP. Novel mutations in RDH5 cause fundus albipunctatus in two consanguineous Pakistani families. Mol Vis 2012; 18: 1558–1571

[25] Albrecht JH, Hansen LK. Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. Cell Growth Differ 1999; 10: 397–404

[26] Végran F, Boidot R, Solary E, Lizard-Nacol S. A short caspase-3 isoform inhibits chemotherapy-induced apoptosis by blocking apoptosome assembly. PLoS One 2011; 6(12): e29058

[27] Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108(2): 153–164

[28] Dlugosz PJ, Billen LP, Annis MG, Zhu W, Zhang Z, Lin J, Leber B, Andrews DW. Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J 2006; 25(11): 2287–2296

[29] Albrecht JH, Hansen LK. Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. Cell Growth Differ 1999; 10(6): 397–404

[30] Fausto N. Liver regeneration. J Hepatol 2000; 32(1 Suppl): 19–31

[31] Coqueret O. Linking cyclins to transcriptional control. Gene 2002; 299(1-2): 35–55

[32] Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006; 43(Suppl 1): S45–S53

[33] Xie Y, Hao H, Wang H, Guo C, Kang A, Wang G. Reversing effects of lignans on CCl₄-induced hepatic CYP450 down regulation by attenuating oxidative stress. J Ethnopharmacol 2014; 155(1): 213–221

[34] Rosenberg DW, Drummond GS, Smith TJ. Depletion of cytochrome P-450 by thyroid hormone and cobalt-protoporphyrin IX in rat liver: evidence that susceptibility varies among forms of the heme protein. Pharmacology 1995; 51(4): 254–262

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