Peroxiredoxin 4 (PRDX4): Its Critical in Vivo Roles in Animal Models of Metabolic Syndrome Ranging from Atherosclerosis to Nonalcoholic Fatty Liver Disease

Pathology International 2018; 68: 91–101 doi:10.1111/pin.12634 Review Article Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease Sohsuke Yamada1 and Xin Guo1,2 1Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, Japan and 2Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Hebei, China The peroxiredoxin (PRDX) family, a new family of proteins molecules and reactive oxygen species (ROS), such as with a pivotal antioxidative function, is ubiquitously synthe- À superoxide anion (O2 ), hydrogen peroxide (H2O2), fi sized and abundantly identi ed in various organisms. In hydroxyl radicals (ÁOH), and the concomitant generation of contrast to the intracellular localization of other family nitric oxide (NO), strongly contribute to the initiation and members (PRDX1/2/3/5/6), PRDX4 is the only known secre- fl tory form and protects against oxidative damage by scaveng- progression of chronic in ammatory diseases, such as 1,2 ing reactive oxygen species in both the intracellular diabetes mellitus (DM) or atherosclerosis. Oxygen (O2), (especially the endoplasmic reticulum) compartments and necessary for the vital activities of living organisms, is the extracellular space. We generated unique human PRDX4 paradoxically a highly reactive molecule and can easily form (hPRDX4) transgenic (Tg) mice on a C57BL/6J background À the one-electron reduction state of O2 , subsequently and investigated the critical and diverse protective roles of resulting in the formation of H2O2, as shown in Fig. 1. PRDX4 against diabetes mellitus, atherosclerosis, insulin Increased oxidative stressors within the extracellular space resistance, and nonalcoholic fatty liver disease (NAFLD) as are considered a risk factor of atherosclerosis due to the well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 accumulation of oxidized low-density lipoprotein (oxLDL) as 3,4 helps prevent the progression of metabolic syndrome by well as the formation of ROS, a feature of chronic reducing local and systemic oxidative stress and synergisti- inflammatory processes. The vascular vessels range from cally suppressing steatosis, inflammatory reactions, and/or small to large sizes, with atherosclerotic lesions histopatho- – apoptotic activity. These observations suggest that Tg mice logically termed “arteriolosclerosis” to “atheroma”.5 7 DM is may be a useful animal model for studying the relevance of closely related to the pathophysiological aspects of arterio- oxidative stress on inflammation and the dysregulation losclerosis, and metabolic syndrome, manifesting as obe- of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators sity, dyslipidemia, type 2 DM and/or atherosclerosis, also of PRDX4 may be useful as therapeutic agents for ameliorat- has a tight correlation with the development of nonalcoholic – ing various chronic inflammatory diseases. fatty liver disease (NAFLD),6 9 which is an umbrella term covering a broad spectrum of clinicopathological presenta- Key words: animal model, chronic inflammatory disease, tions, ranging from simple steatosis to nonalcoholic steato- – human PRDX4 transgenic mice (Tg), metabolic syndrome, hepatitis (NASH).6 12 It is well known that NASH is not only peroxiredoxin (PRDX) 4 a more severe form of NAFLD, occasionally leading to end- stage liver diseases, including cirrhosis and/or hepatocellu- Accumulating evidence has revealed that oxidative stress lar carcinoma (HCC),8–12 but also that oxidative stress and and endoplasmic reticulum (ER) stress, including oxidized ER stress appear to be critically involved in these diseases’ processes, even in animal models.10–14 In fact, oxidative Correspondence: Sohsuke Yamada, MD, PhD, Department of stress appears, at least in part, to mechanistically illustrate Pathology and Laboratory Medicine, Kanazawa Medical University, the endothelial dysfunction, and the vascular inflammation 1-1 Uchinada, Ishikawa 920-0293, Japan. and complications especially in the initiation of the meta- – Email: [email protected] bolic syndrome/metabolic syndrome-related diseases.1 5 Received 12 November 2017. Accepted for publication 13 Furthermore, in addition to the target organs of metabolic December 2017. © 2018 Japanese Society of Pathology and John Wiley & Sons syndrome (arteries and liver), the small intestine with its Australia, Ltd extensive surface area is the first organ to encounter 92 S. Yamada and X. Guo Figure 1 The pathway of the detoxification of reactive oxygen species (ROS) by peroxiredoxin (PRDX). O2 is a highly reactive molecule and can À easily form O2 (superoxide), subsequently undergoing dismutation to form H2O2 (hydrogen peroxide). The functional peroxidase activity of PRDXs is dependent on reduced forms of thioredoxin (redTRX) and/or glutathione (GSH). PRDX, peroxiredoxin; SOD, superoxide dismutase; GSSG, oxidized GSH; GPX, GSH peroxidase; ÁOH, hydroxyl radicals; CoQ, coenzyme Q; p450, cytochrome p450; FAD, flavin adenine dinucleotide. nutrients, which likely plays an important role in the could be highly susceptible to hyperoxidation/inactivation 9,15,16 development of metabolic disorders as well. due to H2O2-mediated sulfonic acid formation on its perox- Taken together, these previous findings and our in vivo idatic Cys,30–34 PRDX4 might be a weak antioxidative data indicate that metabolic syndrome is an extremely enzyme compared to other thiol-dependent antioxidants in complex disease orchestrated by multiple molecular and the context of metabolic syndrome-related diseases. On the histopathologic factors, including not only oxidative stress other hand, PRDX4 is the only known secretory form located but also elevated levels of inflammatory cytokines and in not only the intracellular (especially the ER) but also the apoptotic activity and the translocation of either intestinal extracellular space, in contrast to the intracellular localization bacteria or microbial cell components.6–9,17–29 All research- of other family members (PRDX1, 2 and 6 are located in the ers should be aware of the fact that lipid/bile acid (BA)/ cytoplasm, and PRDX3 and 5 in mitochondria. Moreover, glucose metabolism with both local (each tissue) and several PRDXs, including PRDX4, have also been shown to whole-body functions plays a central, key role in the etiology be nuclear and are among the most abundant pro- of metabolic syndrome. teins).30,31,35,36 PRDX4 has an additional N-terminal region, Peroxiredoxin (PRDX), a new family of antioxidant en- which is unique to this enzyme, following a signal peptide zymes, is ubiquitously synthesized and has been abundantly that allows translocation across the ER membrane and is identified in various organisms.30,31 At least six distinct thereafter cleaved.30,31 Several previous studies have PRDX genes expressed in mammals possess high similari- focused on the molecular regulatory roles of PRDX4 in the ties in their molecular structures and contain a reactive nuclear factor kB(NF-kB),37 epidermal growth factor, and cysteine (Cys) in a conserved region near the N-terminus p53 or thromboxane A2 receptor cascade.36,38 More that forms Cys-sulfenic acid as an intermediate reaction recently, PRDX4 has been reported to play a pivotal role in 31–33 during the reduction of H2O2. As shown in Fig. 1, the disulfide bond formation (i.e. oxidative folding) of lip- PRDXs regulate the H2O2 levels using thioredoxin (TRX) as oproteins in coordination with protein disulfide isomerase an electron donor, and their functional peroxidase activity is (PDI) and ER oxidoreductin 1 (ERO1) in the ER.39,40 dependent on the reduced forms of TRX (redTRX) and/or However, the detailed in vivo pathological and physiological glutathione (GSH).30–33 Fig. 1 summarizes the pathway of relevance of PRDX4 has remained unclear. the detoxification of ROS by PRDXs. Within the PRDX We hypothesized that PRDX4 locally (intracellularly) and family, PRDX4 is a member of the 2-Cys-type PRDX family systemically (extracellularly) plays a critical, diverse role in and homologous to typical 2-Cys PRDX1 and 2, thus serving vivo in the protection against the initiation and development as a TRX-dependent peroxidase via a similar catalytic of metabolic syndrome manifesting as visceral obesity, DM, mechanism to PRDX1/2.31,34 On one hand, since PRDX4 atherosclerosis and/or NAFLD (i.e. disordered lipid/BA/ © 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd PRDX4 in metabolic syndrome 93 glucose metabolism). We generated human PRDX4 NotI fragment containing hPRDX4 cDNA is inserted into the (hPRDX4) transgenic (Tg) mice and evaluated the in vivo NotI site of pcDNA3 (5.4 kb; Invitrogen, Life Technologies functions of PRDX4 in serial studies of various animal Japan, Tokyo, Japan), and the CMV enhancer/promoter of models,5–9 as summarized in Table 1. In the current review, the entire nucleic acid sequence displays extensive cross- we focus on the crucial in vivo roles of PRDX4 in various talk with other promoters since it contains many transcrip- chronic inflammatory diseases, with particular focus on DM, tion factor binding sites, such as NF-kB.5,7–9 However, as it atherosclerosis, and NAFLD. Our findings here suggest that is not a tissue-specific promoter, the protein expression of Tg mice may be a useful animal model for

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