Thymoquinone and quercetin protect against hepatic steatosis in association with SIRT1/AMPK stimulation and regulation of autophagy, perilipin-2, and cytosolic lipases

References

• Ashour, H., et al., 2019. Combined gemfibrozil (peroxisome proliferator-activated receptor alpha agonist) with reduced steroid dose gives a similar management picture as the full steroid dose in a rat adjuvant-induced arthritis model. Modern rheumatology, 29 (4), 602–611. https://doi.org/10.1080/14397595.2018.1508800
   PubMed Web of Science ®Google Scholar
• Atef, Y., et al., 2017. Quercetin and tin protoporphyrin attenuate hepatic ischemia reperfusion injury: role of HO-1. Naunyn-schmiedeberg’s archives of pharmacology, 390 (9), 871–881. https://doi.org/10.1007/s00210-017-1389-9
   PubMed Web of Science ®Google Scholar
• Attia, A., et al., 2010. Attenuation of high cholesterol-induced oxidative stress in rabbit liver by thymoquinone. European journal of gastroenterology & hepatology, 22, 826–834. https://doi.org/10.1097/MEG.0b013e328336000d
   PubMed Web of Science ®Google Scholar
• Awad, A.S.M., et al., 2016. Thymoquinone alleviates nonalcoholic fatty liver disease in rats via suppression of oxidative stress, inflammation, apoptosis. Naunyn-schmiedeberg’s archives of pharmacology, 389 (4), 381–391. https://doi.org/10.1007/s00210-015-1207-1
   PubMed Web of Science ®Google Scholar
• Bai, T., et al., 2014b. Thymoquinone alleviates thioacetamide-induced hepatic fibrosis and inflammation by activating LKB1-AMPK signaling pathway in mice. International immunopharmacology, 19 (2), 351–357. https://doi.org/10.1016/j.intimp.2014.02.006
   PubMed Web of Science ®Google Scholar
• Bai, T., et al., 2014a. Thymoquinone alleviates thioacetamide-induced hepatic fibrosis and inflammation by activating LKB1–AMPK signaling pathway in mice. International immunopharmacology, 19 (2), 351–357. https://doi.org/10.1016/j.intimp.2014.02.006
   PubMed Web of Science ®Google Scholar
• Cantó, C., et al., 2009. AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature, 458 (7241), 1056–1060. https://doi.org/10.1038/nature07813
   PubMed Web of Science ®Google Scholar
• Carling, D., 2017. AMPK signalling in health and disease. Current opinion in cell biology, 45, 31–37. https://doi.org/10.1016/j.ceb.2017.01.005
   PubMed Web of Science ®Google Scholar
• Chan, S.T., et al., 2014. Oral and intraperitoneal administration of quercetin decreased lymphocyte DNA damage and plasma lipid peroxidation induced by TSA in vivo. BioMed research international, 2014, 580626. https://doi.org/10.1155/2014/580626
   PubMed Web of Science ®Google Scholar
• Chen, L., et al., 2020. Quercetin and isoquercitrin inhibiting hepatic gluconeogenesis through lkb1-ampkα pathway. Acta endocrinologica (Bucharest), 16 (1), 9–14. https://doi.org/10.4183/aeb.2020.9
   PubMed Web of Science ®Google Scholar
• Chen, Q., et al., 2017. Effects of natural products on fructose-induced nonalcoholic fatty liver disease (NAFLD). Nutrients, 9 (2), 96. https://doi.org/10.3390/nu9020096
   PubMed Web of Science ®Google Scholar
• Chen, X., et al., 2005. Pharmacokinetics and modeling of quercetin and metabolites. Pharmaceutical research, 22, 892–901. https://doi.org/10.1007/s11095-005-4584-1
   PubMed Web of Science ®Google Scholar
• Dong, J., et al., 2014. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKα1/SIRT1. Journal of lipid research, 55 (3), 363–374. https://doi.org/10.1194/jlr.M038786
   PubMed Web of Science ®Google Scholar
• Drira, R. and Sakamoto, K., 2014. Hydroxytyrosol stimulates lipolysis via A-kinase and extracellular signal-regulated kinase activation in 3T3-L1 adipocytes. European journal of nutrition, 53 (3), 743–750. https://doi.org/10.1007/s00394-013-0578-7
   PubMed Web of Science ®Google Scholar
• Esrefoglu, M., et al., 2017. Therapeutic effects of melatonin and quercetin in improvement of hepatic steatosis in rats through supression of oxidative damage. Bratislavske lekarske listy, 118 (6), 347–354. https://doi.org/10.4149/BLL_2017_066
   PubMed Web of Science ®Google Scholar
• Farghaly, M.E., et al., 2021. Thymoquinone potentiated the anticancer effect of cisplatin on hepatic tumorigenesis by modulating tissue oxidative stress and endoplasmic GRP78/CHOP signaling. Nutrition and cancer, 74, 278–287. https://doi.org/10.1080/01635581.2021.1879880
   PubMed Web of Science ®Google Scholar
• Ferguson, D., et al., 2017. The lipid droplet-associated protein perilipin 3 facilitates hepatitis C virus-driven hepatic steatosis. Journal of lipid research, 58 (2), 420–432. https://doi.org/10.1194/jlr.M073734
   PubMed Web of Science ®Google Scholar
• Galindo, P., et al., 2012. Different cardiovascular protective effects of quercetin administered orally or intraperitoneally in spontaneously hypertensive rats. Food & function, 3 (6), 643–650. https://doi.org/10.1039/c2fo10268d
   PubMed Web of Science ®Google Scholar
• Gauthier, M.-S., et al., 2008. AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte. The journal of biological chemistry, 283 (24), 16514–16524. https://doi.org/10.1074/jbc.M708177200
   PubMed Web of Science ®Google Scholar
• Geisler, C.E. and Renquist, B.J., 2017. Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. The journal of endocrinology, 234 (1), R1–R21. https://doi.org/10.1530/JOE-16-0513
   PubMed Web of Science ®Google Scholar
• Gómez-Zorita, S., et al., 2017. Phenolic compounds apigenin, hesperidin and kaempferol reduce in vitro lipid accumulation in human adipocytes. Journal of translational medicine, 15, 1–10. https://doi.org/10.1186/s12967-017-1343-0
   PubMed Web of Science ®Google Scholar
• Herms, A., et al., 2015. AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation. Nature communications, 6, 7176. https://doi.org/10.1038/ncomms8176
   PubMed Web of Science ®Google Scholar
• Hou, X., et al., 2008. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. The journal of biological chemistry, 283 (29), 20015–20026. https://doi.org/10.1074/jbc.M802187200
   PubMed Web of Science ®Google Scholar
• Jung, C.H., et al., 2013. Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes. Phytotherapy research, 27 (1), 139–143. https://doi.org/10.1002/ptr.4687
   PubMed Web of Science ®Google Scholar
• Kabirifar, R., et al., 2018. Curcumin, quercetin and atorvastatin protected against the hepatic fibrosis by activating AMP-activated protein kinase. Journal of functional foods., 40, 341–348. https://doi.org/10.1016/j.jff.2017.11.020
   Web of Science ®Google Scholar
• Kajikawa, S., et al., 2009. Highly purified eicosapentaenoic acid prevents the progression of hepatic steatosis by repressing monounsaturated fatty acid synthesis in high-fat/high-sucrose diet-fed mice. Prostaglandins, leukotrienes, and essential fatty acids, 80 (4), 229–238. https://doi.org/10.1016/j.plefa.2009.02.004
   PubMed Web of Science ®Google Scholar
• Karandrea, S., et al., 2017. Thymoquinone ameliorates diabetic phenotype in diet-induced obesity mice via activation of SIRT-1-dependent pathways. PLoS one, 12 (9), e0185374. https://doi.org/10.1371/journal.pone.0185374
   PubMed Web of Science ®Google Scholar
• Kaushik, S. and Cuervo, A.M., 2015. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nature cell biology, 17 (6), 759–770. https://doi.org/10.1038/ncb3166
   PubMed Web of Science ®Google Scholar
• Kim, C.S.S., et al., 2016a. Induction of heme oxygenase-1 with dietary quercetin reduces obesity-induced hepatic inflammation through macrophage phenotype switching. Nutrition research and practice, 10 (6), 623–628. https://doi.org/10.4162/nrp.2016.10.6.623
   PubMed Web of Science ®Google Scholar
• Kim, D., et al., 2019. Clinical epidemiology of NAFLD, in: clinical epidemiology of chronic liver diseases. Cham, Switzerland: Springer International Publishing, 211–227. https://doi.org/10.1007/978-3-319-94355-8_14
   Google Scholar
• Kim, J.H., et al., 2016b. Quercetin and quercetin-3-β-d-glucoside improve cognitive and memory function in Alzheimer’s disease mouse. Applied biological chemistry, 59 (5), 721–728. https://doi.org/10.1007/s13765-016-0217-0
   Web of Science ®Google Scholar
• Kim, O.Y., et al., 2012. Influence of quercetin-rich onion peel extracts on adipokine expression in the visceral adipose tissue of rats. Phytotherapy research, 26 (3), 432–437. https://doi.org/10.1002/ptr.3570
   PubMed Web of Science ®Google Scholar
• Kim, S.G., Kim, J.R., and Choi, H.C., 2018. Quercetin-induced AMP-activated protein kinase activation attenuates vasoconstriction through LKB1-AMPK signaling pathway. Journal of medicinal food, 21 (2), 146–153. https://doi.org/10.1089/jmf.2017.4052
   PubMed Web of Science ®Google Scholar
• Kim, S. J., et al., 2016c. AMPK phosphorylates desnutrin/ATGL and hormone-sensitive lipase to regulate lipolysis and fatty acid oxidation within adipose tissue. Molecular and cellular biology, 36 (14), 1961–1976. https://doi.org/10.1128/MCB.00244-16
   PubMed Web of Science ®Google Scholar
• Kobori, M., et al., 2011. Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a Western-style diet in C57/BL6J mice. Molecular nutrition & food research, 55 (4), 530–540. https://doi.org/10.1002/mnfr.201000392
   PubMed Web of Science ®Google Scholar
• Kobori, M., et al., 2016. Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice. Molecular nutrition & food research, 60 (2), 300–312. https://doi.org/10.1002/mnfr.201500595
   PubMed Web of Science ®Google Scholar
• la Fuente, F.P. D., et al., 2019. Exercise regulates lipid droplet dynamics in normal and fatty liver. Biochimica et biophysica acta molecular and cell biology of lipids, 1864 (12), 158519. https://doi.org/10.1016/j.bbalip.2019.158519
   PubMed Web of Science ®Google Scholar
• Lasa, A., et al., 2012. Resveratrol regulates lipolysis via adipose triglyceride lipase. The journal of nutritional biochemistry, 23 (4), 379–384. https://doi.org/10.1016/j.jnutbio.2010.12.014
   PubMed Web of Science ®Google Scholar
• Li, X., et al., 2018. The flavonoid quercetin ameliorates liver inflammation and fibrosis by regulating hepatic macrophages activation and polarization in mice. Frontiers in pharmacology, 9, 72. https://doi.org/10.3389/fphar.2018.00072
   PubMed Web of Science ®Google Scholar
• Liu, P., et al., 2018. Frataxin-mediated PINK1–parkin-dependent mitophagy in hepatic steatosis: the protective effects of quercetin. Molecular nutrition & food research, 62 (16), 1800164–11. https://doi.org/10.1002/mnfr.201800164
   PubMed Web of Science ®Google Scholar
• Livak, K.J. and Schmittgen, T.D., 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2 − ΔΔCT method. Methods, 25 (4), 402–408. https://doi.org/10.1006/meth.2001.1262
   PubMed Web of Science ®Google Scholar
• Madushani Herath, K.H.I.N., et al., 2018. Phenolic acid and flavonoid-rich fraction of Sasa quelpaertensis Nakai leaves prevent alcohol induced fatty liver through AMPK activation. Journal of ethnopharmacology, 224, 335–348. https://doi.org/10.1016/j.jep.2018.06.008
   PubMed Web of Science ®Google Scholar
• Maksymchuk, O., et al., 2017. Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1. Pharmacological reports, 69 (6), 1386–1392. https://doi.org/10.1016/j.pharep.2017.05.020
   PubMed Web of Science ®Google Scholar
• Noorbakhsh, M.-F., et al., 2018. An overview of hepatoprotective effects of thymoquinone. Recent patents on food, nutrition & agriculture, 9 (1), 14–22. https://doi.org/10.2174/2212798410666180221105503
   PubMedGoogle Scholar
• Orlicky, D.J., et al., 2019. Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions. The journal of physiology, 597 (6), 1565–1584. https://doi.org/10.1113/JP277140
   PubMed Web of Science ®Google Scholar
• Prabhakar, P., et al., 2015. Protective effect of thymoquinone against high-fructose diet-induced metabolic syndrome in rats. European journal of nutrition, 54 (7), 1117–1127. https://doi.org/10.1007/s00394-014-0788-7
   PubMed Web of Science ®Google Scholar
• Purushotham, A., et al., 2009. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell metabolism, 9 (4), 327–338. https://doi.org/10.1016/j.cmet.2009.02.006
   PubMed Web of Science ®Google Scholar
• Ruderman, N.B., et al., 2010. AMPK and SIRT1: a long-standing partnership? American journal of physiology endocrinology and metabolism, 298 (4), E751–E760. https://doi.org/10.1152/ajpendo.00745.2009
   PubMed Web of Science ®Google Scholar
• Sanders, M.J., et al., 2007. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. The biochemical journal, 403 (1), 139–148. https://doi.org/10.1042/BJ20061520
   PubMedGoogle Scholar
• Sathyanarayan, A., Mashek, M.T., and Mashek, D.G., 2017. ATGL promotes autophagy/lipophagy via SIRT1 to control hepatic lipid droplet catabolism. Cell reports, 19 (1), 1–9. https://doi.org/10.1016/j.celrep.2017.03.026
   PubMed Web of Science ®Google Scholar
• Sedaghat, R., Roghani, M., and Khalili, M., 2014. Neuroprotective effect of thymoquinone, the Nigella Sativa bioactive compound. Iranian journal of pharmaceutical research, 13 (1), 227–234.
   PubMed Web of Science ®Google Scholar
• Seyithanoğlu, M., et al., 2016. The effect of dietary curcumin and capsaicin on hepatic fetuin-A expression and fat accumulation in rats fed on a high-fat diet. Archives of physiology and biochemistry, 122 (2), 94–102. https://doi.org/10.3109/13813455.2015.1120753
   PubMed Web of Science ®Google Scholar
• Shi, Y., et al., 2019. The prevalence of lean/nonobese nonalcoholic fatty liver disease. Journal of clinical gastroenterology, 54, 378–387. https://doi.org/10.1097/MCG.0000000000001270
   Web of Science ®Google Scholar
• Singh, R. and Cuervo, A.M., 2012. Lipophagy: connecting autophagy and lipid metabolism. International journal of cell biology, 2012, 282041–12. https://doi.org/10.1155/2012/282041
   PubMedGoogle Scholar
• Snyder, S.M., et al., 2016. Consumption of quercetin and quercetin-containing apple and cherry extracts affects blood glucose concentration, hepatic metabolism, and gene expression patterns in obese C57BL/6J high fat–fed mice. The journal of nutrition, 146 (5), 1001–1007. https://doi.org/10.3945/jn.115.228817
   PubMed Web of Science ®Google Scholar
• Takahashi, Y. and Fukusato, T., 2014. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World journal of gastroenterology, 20 (42), 15539–15548. https://doi.org/10.3748/wjg.v20.i42.15539
   PubMed Web of Science ®Google Scholar
• Tang, Y., et al., 2012. Quercetin prevents ethanol-induced dyslipidemia and mitochondrial oxidative damage. Food and chemical toxicology, 50, 1194–1200. https://doi.org/10.1016/j.fct.2012.02.008
   Google Scholar
• Vissiennon, C., et al., 2012. Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin - are they prodrugs? Journal of nutritional biochemistry, 23, 733–740. https://doi.org/10.1016/j.jnutbio.2011.03.017
   PubMed Web of Science ®Google Scholar
• Walther, T.C., Chung, J., and Farese, R.V., 2017. Lipid droplet biogenesis. Annual review of cell and developmental biology, 33, 491–510. https://doi.org/10.1146/annurev-cellbio-100616-060608
   PubMed Web of Science ®Google Scholar
• Wang, M., et al., 2020. Quercetin improving lipid metabolism by regulating lipid metabolism pathway of ileum mucosa in broilers. Oxidative medicine and cellular longevity, 2020, 1–17. https://doi.org/10.1155/2020/8686248
   Google Scholar
• Wang, W., et al., 2013. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. British journal of pharmacology, 169 (6), 1352–1371. https://doi.org/10.1111/bph.12226
   PubMed Web of Science ®Google Scholar
• Xue, B. and Kahn, B.B., 2006. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. The journal of physiology, 574 (Pt 1), 73–83. https://doi.org/10.1113/jphysiol.2006.113217
   PubMed Web of Science ®Google Scholar
• Yang, H., et al., 2019. Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice. Phytotherapy research, 33 (12), 3140–3152. https://doi.org/10.1002/ptr.6486
   PubMed Web of Science ®Google Scholar
• Yang, Y., et al., 2016. Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicology letters, 262, 80–91. https://doi.org/10.1016/j.toxlet.2016.09.014
   PubMed Web of Science ®Google Scholar
• Younossi, Z., et al., 2019. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology, 69 (6), 2672–2682. https://doi.org/10.1002/hep.30251
   PubMed Web of Science ®Google Scholar
• Yu, X., et al., 2016. Quercetin attenuates chronic ethanol-induced hepatic mitochondrial damage through enhanced mitophagy. Nutrients, 8 (1), 27. https://doi.org/10.3390/nu8010027
   PubMed Web of Science ®Google Scholar
• Zeng, H., et al., 2019. Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy. Food and chemical toxicology, 125, 21–28. https://doi.org/10.1016/j.fct.2018.12.028
   PubMed Web of Science ®Google Scholar
• Zhu, J., et al., 2019. Phosphorylation of PLIN3 by AMPK promotes dispersion of lipid droplets during starvation. Protein & cell, 10 (5), 382–387. https://doi.org/10.1007/s13238-018-0593-9
   PubMed Web of Science ®Google Scholar