Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 1191 word(s) 1191 2021-11-14 03:29:36 |
2 format corrected. -4 word(s) 1187 2021-11-19 05:18:50 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Li, J. Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis. Encyclopedia. Available online: https://encyclopedia.pub/entry/16179 (accessed on 28 March 2024).
Li J. Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis. Encyclopedia. Available at: https://encyclopedia.pub/entry/16179. Accessed March 28, 2024.
Li, Jingjing. "Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis" Encyclopedia, https://encyclopedia.pub/entry/16179 (accessed March 28, 2024).
Li, J. (2021, November 19). Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis. In Encyclopedia. https://encyclopedia.pub/entry/16179
Li, Jingjing. "Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis." Encyclopedia. Web. 19 November, 2021.
Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis
Edit

Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.

fatty liver disease lipid metabolism OTA PPAR

1. Introduction

Ochratoxin A (OTA) is produced by several species of Aspergillus and Penicillium [1], and is one of the most common mycotoxin contaminant in food. It has been identified in various crops, including cereals and cereal products, coffee beans, peanuts, dried fruits, spices, legumes, wine and beer [2]. OTA has long been studied as a nephrotoxin, immunotoxin, teratogen and carcinogen in humans as well as other animal species [3][4][5][6], and is regarded to be a nonnegligible risk of human health because of its widespread occurrence. This mycotoxin is metabolized and accumulated mainly in the liver and kidney [7], which are the major target organs for OTA [8].
Liver is a vital metabolic organ in the maintenance of whole-body homeostasis. Because liver is responsible for metabolism, distribution and excretion of exogenous chemicals, it is threatened by significant concentrations of chemicals, and chemical- or drug-induced liver injury (hepatotoxicity). Furthermore, it is recently suggested that nonalcoholic fatty liver disease (NAFLD), or steatosis, is the most prevalent pathology associated with toxicant exposure [9]. In particular, OTA affects hepatocytes via multiple pathways, including oxidative stress [10][11], inflammation [12], apoptosis [13][14][15] and genotoxic effect [16][17], It is reported that OTA would increase the expression of genes involved in the synthesis of fatty acid in kidney. In contrast, it significantly inhibited the expression of genes related to fatty acid oxidation [18]. However, the lipotoxicity of OTA in liver remains unknown.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives [19]. There are three PPAR isotypes—α, β/δ and γ, they are well known to serve as important regulatory factors of lipid metabolism. PPARα modulates transcription of specific target genes involved in lipid oxidation, lipid transport, lipoprotein assembly and ketogenesis [20]. PPARβ/δ is most abundant in metabolically active tissues such as skeletal and cardiac muscle, and regulates lipid metabolism, inflammation and oxidative stress responses [21][22]. PPARγ plays a role in regulating adipocyte differentiation and energy storage in mature adipocytes [23]. Thus, PPARs are promising drug targets for the management of NAFLD.
The influence of OTA on hepatic lipid metabolism was investigated. It's found that OTA increased lipid droplets deposition and TG accumulation in primary hepatocytes and HepG2 cells, and induced steatosis in mice. The mechanistic study revealed that OTA disturbed lipid metabolism in liver cells mainly through PPARγ-CD36 axis. OTA can stabilize PPARγ via preventing its ubiquitination and subsequent degradation. Therefore, our study provides novel insights into the mechanism underlying the disturbance of hepatic lipid metabolism by OTA.

2. Insights and Summary

OTA is considered to be one of the most important contaminants of global food and crops. Ambient temperature, humidity, food storage and transportation may promote fungal growth leading to increased occurrence of OTA in various crops [24]. OTA has been detected in human blood and serum in Canada, Sweden, West Germany and Yugoslavia [25], suggesting the high incidence of OTA exposure in human. Therefore, there is a need to investigate the toxic effects of OTA for prevention.
Previous studies reported that inhibition on protein synthesis and energy generation, induction of oxidative stress, apoptosis/necrosis, DNA adduct formation and cell cycle arrest were possibly involved in OTA toxicity. OTA intake increased some marker of liver damage such as AST, ALT, GGT and ALP [26], which may be caused by OTA-induced oxidative damage [27] and apoptosis [28]. OTA was reported to enhance lipid peroxidation [29][30], however, its influence on other aspects of lipid metabolism remains largely unknown. In the present study, we found that OTA increased lipid deposition and TG accumulation in liver, which revealed its influence on hepatic lipid metabolism and its risk to induce NAFLD. These findings have improved our understanding of this fungal toxin.
PPARs are representative members of nuclear receptors. This large superfamily is capable of ligand binding, which modulates their activities to regulate gene expression [31]. It has been determined that fatty acids and their derivatives bind and activate PPAR proteins [32]. Therefore, PPARs are important regulators to maintain cellular metabolic homeostasis. Lim et al. reported that OTA notably reduced the expression of adipocyte-specific genes, including PPARγ, therefore inhibited adipogenesis in mesenchymal stem cells derived from human adipose tissue [33]. In contrast, we found that PPARγ protein expression was increased in the livers after OTA treatment, whereas the mRNA level was comparable with control livers. This inconsistence may be attributed to the different cell types. It was reported that prolonged OTA exposure decreased ubiquitination levels of proteins by promoting proteasome activity [34]. However, we observed that OTA increased the PPARγ protein level in our study. We found that the interaction between PPARγ and its E3 ligase SIAH2 was reduced upon OTA treatment. Consequently, OTA prevented degradation of PPARγ. Therefore, OTA may influence protein stability in different ways.
Consistent with the increased expression and activity of PPARγ upon OTA treatment, the expression of CD36, a target of PPARγ [35] was increased in vivo and in vitro upon OTA treatment. CD36 is an important mediator of lipid uptake in many tissues, and abnormal CD36 expression in the liver resulted in TG accumulation and the development of hepatic steatosis [36]. As expected, OTA-induced lipid droplets formation and TG accumulation was alleviated in CD36 knockdown cells. FABP2 is involved in fatty acid transportation [37], and is another downstream target of PPARγ. Similar to CD36, expression of FABP2 was also increased after OTA treatment. Knockdown of FABP2 reduced lipid droplets accumulation, but had no effect on TG contents. We noticed that OTA also upregulated the expression of two other FABPs, FABP1 and FABP3 (Figure 4d), although the alteration was less significant than FABP2. These FABPs may compensate for knockdown of FABP2, which contributed to the modest effect on lipid metabolism caused by FABP2 silencing. Therefore, CD36 seems the predominant effector downstream of PPARγ to mediate the effect of OTA on hepatic lipid metabolism.
In summary, the current study demonstrated that long-term exposure to OTA induces lipid accumulation in the liver of mice, mainly through activation of PPARγ signaling via post-translational modification of this nuclear receptor. The study not only reveals the novel hepatic toxicity of OTA other than ROS generation and apoptosis induction, but also highlights the risk of OTA to cause NAFLD.

References

  1. Ringot, D.; Chango, A.; Schneider, Y.-J.; Larondelle, Y. Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem. Biol. Interact. 2006, 159, 18–46.
  2. Hajok, I.; Kowalska, A.; Piekut, A.; Ćwieląg-Drabek, M. A risk assessment of dietary exposure to ochratoxin A for the Polish population. Food Chem. 2019, 284, 264–269.
  3. Clarke, R.; Connolly, L.; Frizzell, C.; Elliott, C.T. Challenging conventional risk assessment with respect to human exposure to multiple food contaminants in food: A case study using maize. Toxicol. Lett. 2015, 238, 54–64.
  4. Bui-Klimke, T.R.; Wu, F. Ochratoxin A and Human Health Risk: A Review of the Evidence. Crit. Rev. Food Sci. Nutr. 2015, 55, 1860–1869.
  5. Damiano, S.; Iovane, V.; Squillacioti, C.; Mirabella, N.; Prisco, F.; Ariano, A.; Amenta, M.; Giordano, A.; Florio, S.; Ciarcia, R. Red orange and lemon extract prevents the renal toxicity induced by ochratoxin A in rats. J. Cell. Physiol. 2020, 235, 5386–5393.
  6. Bendele, A.M.; Carlton, W.W.; Krogh, P.; Lillehoj, E.B. Ochratoxin A carcinogenesis in the (C57BL/6J X C3H)F1 mouse. J. Natl. Cancer Inst. 1985, 75, 733–742.
  7. Rached, E.; Hard, G.; Blumbach, K.; Weber, K.; Draheim, R.; Lutz, W.; Ozden, S.; Steger, U.; Dekant, W.; Mally, A. Ochratoxin A: 13-Week Oral Toxicity and Cell Proliferation in Male F344/N Rats. Toxicol. Sci. Off. J. Soc. Toxicol. 2007, 97, 288–298.
  8. Vettorazzi, A.; Trocóniz, I.; González-Peñas, E.; Arbillaga, L.; Corcuera, L.; Gil, A.; Cerain, A. Kidney and liver distribution of ochratoxin A in male and female F344 rats. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2011, 49, 1935–1942.
  9. Al-Eryani, L.; Wahlang, B.; Falkner, K.C.; Guardiola, J.J.; Clair, H.B.; Prough, R.A.; Cave, M. Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents. Toxicol. Pathol. 2015, 43, 482–497.
  10. Shin, H.; Lee, H.J.; Pyo, M.C.; Ryu, D.; Lee, K. Ochratoxin A-Induced Hepatotoxicity through Phase I and Phase II Reactions Regulated by AhR in Liver Cells. Toxins 2019, 11, 377.
  11. Ramyaa, P.; Krishnaswamy, R.; Padma, V.V. Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells—Up regulation of Nrf2 expression and down regulation of NF-κB and COX-2. Biochim. Biophys. Acta 2014, 1840, 681–692.
  12. Wang, W.; Zhai, S.; Xia, Y.; Wang, H.; Ruan, D.; Zhou, T.; Zhu, Y.; Zhang, H.; Zhang, M.; Ye, H.; et al. Ochratoxin A induces liver inflammation: Involvement of intestinal microbiota. Microbiome 2019, 7, 151.
  13. Wang, H.; Wei, Y.; Xie, Y.; Yan, C.; Du, H.; Li, Z. Ochratoxin A and fumonisin B1 exhibit synergistic cytotoxic effects by inducing apoptosis on rat liver cells. Toxicon 2020, 181, 19–27.
  14. Atroshi, F.; Biese, I.; Saloniemi, H.; Ali-Vehmas, T.; Saari, S.; Rizzo, A.; Veijalainen, P. Significance of apoptosis and its relationship to antioxidants after ochratoxin A administration in mice. J. Pharm. Pharm. Sci. 2000, 3, 281–291.
  15. Chopra, M.; Link, P.; Michels, C.; Schrenk, D. Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes. Cell Biol. Toxicol. 2010, 26, 239–254.
  16. Ehrlich, V.; Darroudi, F.; Uhl, M.; Steinkellner, H.; Gann, M.; Majer, B.; Eisenbauer, M.; Knasmüller, S. Genotoxic effects of ochratoxin A in human-derived hepatoma (HepG2) cells. Food Chem. Toxicol. 2002, 40, 1085–1090.
  17. Gayathri, L.; Dhivya, R.; Dhanasekaran, D.; Periasamy, V.S.; Alshatwi, A.A.; Akbarsha, M.A. Hepatotoxic effect of ochratoxin A and citrinin, alone and in combination, and protective effect of vitamin E: In vitro study in HepG2 cell. Food Chem. Toxicol. 2015, 83, 151–163.
  18. Yang, X.; Xu, W.-T.; Huang, K.; Zhang, B.; Wang, H.; Zhang, X.; Gong, L.; Luo, Y.; Xiaoyun, H. Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity. FASEB J. 2018, 33, fj.201800742R.
  19. Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr. Rev. 1999, 20, 649–688.
  20. Brocker, C.N.; Patel, D.P.; Velenosi, T.J.; Kim, D.; Yan, T.; Yue, J.; Li, G.; Krausz, K.W.; Gonzalez, F.J. Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice. J. Lipid Res. 2018, 59, 2140–2152.
  21. Koh, J.H.; Hancock, C.R.; Terada, S.; Higashida, K.; Holloszy, J.O.; Han, D.H. PPARβ Is Essential for Maintaining Normal Levels of PGC-1α and Mitochondria and for the Increase in Muscle Mitochondria Induced by Exercise. Cell Metab. 2017, 25, 1176–1185.e5.
  22. Georgiadi, A.; Lichtenstein, L.; Degenhardt, T.; Boekschoten, M.V.; van Bilsen, M.; Desvergne, B.; Müller, M.; Kersten, S. Induction of cardiac Angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor beta/delta and protects against fatty acid-induced oxidative stress. Circ. Res. 2010, 106, 1712–1721.
  23. Gavrilova, O.; Haluzik, M.; Matsusue, K.; Cutson, J.J.; Johnson, L.; Dietz, K.R.; Nicol, C.J.; Vinson, C.; Gonzalez, F.J.; Reitman, M.L. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J. Biol. Chem. 2003, 278, 34268–34276.
  24. Zain, M.E. Impact of mycotoxins on humans and animals. J. Saudi Chem. Soc. 2011, 15, 129–144.
  25. Bennett, J.W.; Klich, M. Mycotoxins. Encycl. Microbiol. 2009, 16, 559–565.
  26. Hanif, N.Q.; Muhammad, G.; Siddique, M.; Khanum, A.; Ahmed, T.; Gadahai, J.A.; Kaukab, G. Clinico-pathomorphological, serum biochemical and histological studies in broilers fed ochratoxin A and a toxin deactivator (Mycofix Plus). Br. Poult. Sci. 2008, 49, 632–642.
  27. Damiano, S.; Longobardi, C.; Andretta, E.; Prisco, F.; Piegari, G.; Squillacioti, C.; Montagnaro, S.; Pagnini, F.; Badino, P.; Florio, S.; et al. Antioxidative Effects of Curcumin on the Hepatotoxicity Induced by Ochratoxin A in Rats. Antioxidants 2021, 10, 125.
  28. Longobardi, C.; Damiano, S.; Andretta, E.; Prisco, F.; Russo, V.; Pagnini, F.; Florio, S.; Ciarcia, R. Curcumin Modulates Nitrosative Stress, Inflammation, and DNA Damage and Protects against Ochratoxin A-Induced Hepatotoxicity and Nephrotoxicity in Rats. Antioxidants 2021, 10, 1239.
  29. Kumar, M.; Dwivedi, P.; Sharma, A.K.; Sankar, M.; Patil, R.D.; Singh, N.D. Apoptosis and lipid peroxidation in ochratoxin A- and citrinin-induced nephrotoxicity in rabbits. Toxicol. Ind. Health 2014, 30, 90–98.
  30. Soyöz, M.; Ozçelik, N.; Kilinç, I.; Altuntaş, I. The effects of ochratoxin A on lipid peroxidation and antioxidant enzymes: A protective role of melatonin. Cell Biol. Toxicol. 2004, 20, 213–219.
  31. Cave, M.C.; Clair, H.B.; Hardesty, J.E.; Falkner, K.C.; Feng, W.; Clark, B.J.; Sidey, J.; Shi, H.; Aqel, B.A.; McClain, C.J.; et al. Nuclear receptors and nonalcoholic fatty liver disease. Biochim. Biophys. Acta 2016, 1859, 1083–1099.
  32. Hong, F.; Pan, S.; Guo, Y.; Xu, P.; Zhai, Y. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism. Molecules 2019, 24, 2545.
  33. Lim, S.; Jang, H.J.; Kim, J.K.; Kim, J.M.; Park, E.H.; Yang, J.H.; Kim, Y.H.; Yea, K.; Ryu, S.H.; Suh, P.G. Ochratoxin A inhibits adipogenesis through the extracellular signal-related kinases-peroxisome proliferator-activated receptor-γ pathway in human adipose tissue-derived mesenchymal stem cells. Stem Cells Dev. 2011, 20, 415–426.
  34. Akpinar, H.A.; Kahraman, H.; Yaman, I. Ochratoxin A Sequentially Activates Autophagy and the Ubiquitin-Proteasome System. Toxins 2019, 11, 615.
  35. Zhou, J.; Febbraio, M.; Wada, T.; Zhai, Y.; Xie, W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008, 134, 556–567.e1.
  36. Koonen, D.P.; Jacobs, R.L.; Febbraio, M.; Young, M.E.; Soltys, C.L.; Ong, H.; Vance, D.E.; Dyck, J.R. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 2007, 56, 2863–2871.
  37. Storch, J.; McDermott, L. Structural and functional analysis of fatty acid-binding proteins. J. Lipid Res. 2009, 50, S126–S131.
More
Information
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 361
Revisions: 2 times (View History)
Update Date: 19 Nov 2021
1000/1000