Abstract
As alcohol consumption increases, alcoholic liver disease (ALD) has become more popular and is threating our human life. In this study, we found mulberry fruit extract (MFE) repaired alcohol-caused liver diseases by regulating hepatic lipid biosynthesis pathway and oxidative singling in alcoholically liver injured (ALI) rats. MFE administration inhibited hepatic lipid accumulation and improved liver steatosis in ALI rats. MFE also enhanced the antioxidant capacity and alleviated the inflammatory response by increasing the activities of antioxidant enzymes and decreasing the contents of interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Additionally, MFE regulated the expression of miRNA-155 and lipid metabolism–related PPARα protein in rats. Both miR-155 and PPARα play important roles in liver function. The results indicate that MFE has hepatoprotective effects against ALI in rats.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data and materials were presented in this paper, which will be available when requested.
References
Albillos A, de Gottardi A, Rescigno M (2020) The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol 72(3):558–577. https://doi.org/10.1016/j.jhep.2019.10.003
Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355. https://doi.org/10.1038/nature02871
Bala S, Csak T, Saha B, Zatsiorsky J, Kodys K, Catalano D, Satishchandran A, Szabo G (2016) The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. J Hepatol 64(6):1378–1387. https://doi.org/10.1016/j.jhep.2016.01.035
Bala S, Ganz M, Babuta M, Zhuang Y, Csak T, Calenda CD, Szabo G (2021) Steatosis, inflammasome upregulation, and fibrosis are attenuated in miR-155 deficient mice in a high fat-cholesterol-sugar diet-induced model of NASH. Lab Invest 101(12):1540–1549. https://doi.org/10.1038/s41374-021-00626-1
Bala S, Marcos M, Kodys K, Csak T, Catalano D, Mandrekar P, Szabo G (2011) Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem 286(2):1436–1444. https://doi.org/10.1074/jbc.M110.145870
Bala S, Szabo G (2012) MicroRNA signature in alcoholic liver disease. Int J Hepatol 2012:498232. https://doi.org/10.1155/2012/498232
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297. https://doi.org/10.1016/s0092-8674(04)00045-5
Bayraktar R, Van Roosbroeck K (2018) miR-155 in cancer drug resistance and as target for miRNA-based therapeutics. Cancer Metastasis Rev 37(1):33–44. https://doi.org/10.1007/s10555-017-9724-7
Beni FA, Kazemi M, Dianat-Moghadam H et al (2022) MicroRNAs regulating Wnt signaling pathway in colorectal cancer: biological implications and clinical potentials. Funct Integr Genomics 22:1073–1088. https://doi.org/10.1007/s10142-022-00908-x
Blaya D, Aguilar-Bravo B, Hao F et al (2018) Expression of microRNA-155 in inflammatory cells modulates liver injury. Hepatology 68(2):691–706. https://doi.org/10.1002/hep.29833
Chen J, Chen J, Fu H, Li Y, Wang L, Luo S, Lu H (2019) Hypoxia exacerbates nonalcoholic fatty liver disease via the HIF-2alpha/PPARalpha pathway. Am J Physiol Endocrinol Metab 317(4):E710–E722. https://doi.org/10.1152/ajpendo.00052.2019
Cheng KC, Wang CJ, Chang YC, Hung TW, Lai CJ, Kuo CW, Huang HP (2020) Mulberry fruits extracts induce apoptosis and autophagy of liver cancer cell and prevent hepatocarcinogenesis in vivo. J Food Drug Anal 28(1):84–93. https://doi.org/10.1016/j.jfda.2019.06.002
Christofides A, Konstantinidou E, Jani C, Boussiotis VA (2021) The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism 114:154338. https://doi.org/10.1016/j.metabol.2020.154338
Church RJ, Watkins PB (2019) Serum biomarkers of drug-induced liver injury: Current status and future directions. J Dig Dis 20(1):2–10. https://doi.org/10.1111/1751-2980.12684
Dalmagro AP, Camargo A, Severo RA, Zeni A (2019) Involvement of PI3K/Akt/GSK-3beta signaling pathway in the antidepressant-like and neuroprotective effects of Morus nigra and its major phenolic, syringic acid. Chem Biol Interact 314:108843. https://doi.org/10.1016/j.cbi.2019.108843
Doghish AS, Elballal MS, Elazazy O, Elesawy AE, Elrebehy MA, Shahin RK, Midan HM, Sallam AM (2023) The role of miRNAs in liver diseases: Potential therapeutic and clinical applications. Pathol Res Pract 243:154375. https://doi.org/10.1016/j.prp.2023.154375
Fuenzalida C, Dufeu MS, Poniachik J, Roblero JP, Valenzuela-Perez L, Beltran CJ (2021) Probiotics-Based Treatment as an Integral Approach for Alcohol Use Disorder in Alcoholic Liver Disease. Front Pharmacol 12:729950. https://doi.org/10.3389/fphar.2021.729950
Gao Y, Tian R, Liu H, Xue H, Zhang R, Han S, Ji L, Huang W, Zhan J, You Y (2022) Research progress on intervention effect and mechanism of protocatechuic acid on nonalcoholic fatty liver disease. Crit Rev Food Sci Nutr 62(32):9053–9075. https://doi.org/10.1080/10408398.2021.1939265
Hammond SM (2015) An overview of microRNAs. Adv Drug Deliv Rev 87:3–14. https://doi.org/10.1016/j.addr.2015.05.001
Han KH, Hashimoto N, Fukushima M (2016) Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes. World J Gastroenterol 22(1):37–49. https://doi.org/10.3748/wjg.v22.i1.37
Hartmann P, Seebauer CT, Schnabl B (2015) Alcoholic liver disease: the gut microbiome and liver cross talk. Alcohol Clin Exp Res 39(5):763–775. https://doi.org/10.1111/acer.12704
Hartmann P, Tacke F (2016) Tiny RNA with great effects: miR-155 in alcoholic liver disease. J Hepatol 64(6):1214–1216. https://doi.org/10.1016/j.jhep.2016.02.039
Hu J, Huang S, Liu X, Zhang Y, Wei S, Hu X (2022) miR-155: an important role in inflammation response. J Immunol Res 2022:7437281. https://doi.org/10.1155/2022/7437281
Iwakiri Y, Kim MY (2015) Nitric oxide in liver diseases. Trends Pharmacol Sci 36(8):524–536. https://doi.org/10.1016/j.tips.2015.05.001
Kersten S, Stienstra R (2017) The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. Biochimie 136:75–84. https://doi.org/10.1016/j.biochi.2016.12.019
Kim YS, Lee HM, Kim JK, Yang CS, Kim TS, Jung M, Jin HS, Kim S, Jang J, Oh GT, Kim JM, Jo EK (2017) PPAR-alpha activation mediates innate host defense through induction of TFEB and lipid catabolism. J Immunol 198(8):3283–3295. https://doi.org/10.4049/jimmunol.1601920
Kong LZ, Chandimali N, Han YH, Lee DH, Kim JS, Kim SU, Kim TD, Jeong DK, Sun HN, Lee DS, Kwon T (2019) Pathogenesis, early diagnosis, and therapeutic management of alcoholic liver disease. Int J Mol Sci 20(11):2712. https://doi.org/10.3390/ijms20112712
Kong L, Chen J, Ji X, Qin Q, Yang H, Liu D, Li D, Sun M (2021) Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARalpha to activate the NF-kappaB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance. J Exp Clin Cancer Res 40(1):18. https://doi.org/10.1186/s13046-020-01782-w
Lai JR, Hsu YW, Pan TM, Lee CL (2021) Monascin and Ankaflavin of Monascus purpureus prevent alcoholic liver disease through regulating AMPK-mediated lipid metabolism and enhancing both anti-inflammatory and anti-oxidative systems. Molecules 26(20):6301. https://doi.org/10.3390/molecules26206301
Lamas-Paz A, Hao F, Nelson LJ, Vazquez MT, Canals S, Gómez Del Moral M, Martínez-Naves E, Nevzorova YA, Cubero FJ (2018) Alcoholic liver disease: utility of animal models. World J Gastroenterol 24(45):5063–5075. https://doi.org/10.3748/wjg.v24.i45.5063
Lee D, Yu JS, Lee SR, Hwang GS, Kang KS, Park JG, Kim HY, Kim KH, Yamabe N (2018) Beneficial effects of bioactive compounds in mulberry fruits against cisplatin-induced nephrotoxicity. Int J Mol Sci 19(4):1117. https://doi.org/10.3390/ijms19041117
Lee S, Lee J, Lee H, Sung J (2019) Relative protective activities of quercetin, quercetin-3-glucoside, and rutin in alcohol-induced liver injury. J Food Biochem 43(11):e13002. https://doi.org/10.1111/jfbc.13002
Li LX, Guo FF, Liu H, Zeng T (2022) Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets. Cell Mol Life Sci 79(4):201. https://doi.org/10.1007/s00018-022-04239-9
Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16(11):26087–26124. https://doi.org/10.3390/ijms161125942
Li Z, Han S, Jia Y, Yang Y, Han F, Wu G, Li X, Zhang W, Jia W, He X, Han J, Hu D (2019) MCPIP1 regulates RORalpha expression to protect against liver injury induced by lipopolysaccharide via modulation of miR-155. J Cell Physiol 234(9):16562–16572. https://doi.org/10.1002/jcp.28327
Lim SH, Choi CI (2019) Pharmacological properties of Morus nigra L. (Black Mulberry) as a promising nutraceutical resource. Nutrients 11(2):437. https://doi.org/10.3390/nu11020437
Liu Q, Pan R, Ding L, Zhang F, Hu L, Ding B, Zhu L, Xia Y, Dou X (2017) Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. Int Immunopharmacol 49:132–141. https://doi.org/10.1016/j.intimp.2017.05.026
Louvet A, Mathurin P (2015) Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 12(4):231–242. https://doi.org/10.1038/nrgastro.2015.35
Lu Y, Shao M, Xiang H, Wang J, Ji G, Wu T (2022) Qinggan Huoxue recipe alleviates alcoholic liver injury by suppressing endoplasmic reticulum stress through LXR-LPCAT3. Front Pharmacol 13:824185. https://doi.org/10.3389/fphar.2022.824185
Luo R, Yi Z, Wu W, Meng W (2021) The mRNA levels of PPARalpha, HIF-1alpha, and VEGF in the liver tissues of rats with alcoholic liver disease. Am J Transl Res 13(10):11932–11937
Meroni M, Longo M, Rametta R, Dongiovanni P (2018) Genetic and epigenetic modifiers of alcoholic liver disease. Int J Mol Sci 19(12):3857. https://doi.org/10.3390/ijms19123857
Montagner A, Polizzi A, Fouche E et al (2016) Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65(7):1202–1214. https://doi.org/10.1136/gutjnl-2015-310798
Nakajima T, Kamijo Y, Tanaka N et al (2004) Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage. Hepatology 40(4):972–980. https://doi.org/10.1002/hep.20399
Ohashi K, Pimienta M, Seki E (2018) Alcoholic liver disease: a current molecular and clinical perspective. Liver Res 2(4):161–172. https://doi.org/10.1016/j.livres.2018.11.002
Osna NA, Donohue TJ, Kharbanda KK (2017) Alcoholic Liver disease: pathogenesis and current management. Alcohol Res 38(2):147–161
Panyod S, Wu WK, Ho CT, Lu KH, Liu CT, Chu YL, Lai YS, Chen WC, Lin YE, Lin SH, Sheen LY (2016) Diet supplementation with allicin protects against alcoholic fatty liver disease in mice by improving anti-inflammation and antioxidative functions. J Agric Food Chem 64(38):7104–7113. https://doi.org/10.1021/acs.jafc.6b02763
Pasqualotto A, Ayres R, Longo L, Del DLD, Losch DOD, Alvares-Da-Silva MR, Reverbel da Silveira T, Uribe-Cruz C (2021) Chronic exposure to ethanol alters the expression of miR-155, miR-122 and miR-217 in alcoholic liver disease in an adult zebrafish model. Biomarkers 26(2):146–151. https://doi.org/10.1080/1354750X.2021.1874051
Qiao JY, Li HW, Liu FG, Li YC, Tian S, Cao LH, Hu K, Wu XX, Miao MS (2019) Effects of Portulaca Oleracea extract on acute alcoholic liver injury of rats. Molecules 24(16):2887. https://doi.org/10.3390/molecules24162887
Qin G, Ma J, Huang Q, Yin H, Han J, Li M, Deng Y, Wang B, Hassan W, Shang J (2018) Isoquercetin improves hepatic lipid accumulation by activating AMPK pathway and suppressing TGF-beta signaling on an HFD-induced nonalcoholic fatty liver disease rat model. Int J Mol Sci 19(12):4126. https://doi.org/10.3390/ijms19124126
Rabelo ACS, de Pádua LK, Araújo CM, de Araújo GR, de Amorim Miranda PH, Carneiro ACA, de Castro Ribeiro ÉM, de Melo SB, de Lima WG, Costa DC (2018) Baccharis trimera protects against ethanol induced hepatotoxicity in vitro and in vivo. J Ethnopharmacol 215:1–13. https://doi.org/10.1016/j.jep.2017.12.043
Ress C, Kaser S (2016) Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol 22(4):1664–1673. https://doi.org/10.3748/wjg.v22.i4.1664
Sid B, Verrax J, Calderon PB (2013) Role of oxidative stress in the pathogenesis of alcohol-induced liver disease. Free Radic Res 47(11):894–904. https://doi.org/10.3109/10715762.2013.819428
Szabo G, Bala S (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10(9):542–552. https://doi.org/10.1038/nrgastro.2013.87
Torres JL, Novo-Veleiro I, Manzanedo L, Alvela-Suarez L, Macias R, Laso FJ, Marcos M (2018) Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease. World J Gastroenterol 24(36):4104–4118. https://doi.org/10.3748/wjg.v24.i36.4104
Wang RS, Dong PH, Shuai XX, Chen MS (2022) Evaluation of different black mulberry fruits (Morus nigra L.) based on phenolic compounds and antioxidant activity. Foods 11(9):1252. https://doi.org/10.3390/foods11091252
Wang W, Bian H, Li F, Li X, Zhang D, Sun S, Song S, Zhu Q, Ren W, Qin C, Qi J (2018) HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines. Cell Mol Life Sci 75(14):2627–2641. https://doi.org/10.1007/s00018-018-2753-8
Wang X, He Y, Mackowiak B, Gao B (2021) MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 70(4):784–795. https://doi.org/10.1136/gutjnl-2020-322526
Wang Y, Nakajima T, Gonzalez FJ, Tanaka N (2020) PPARs as metabolic regulators in the liver: lessons from liver-specific PPAR-null mice. Int J Mol Sci 21(6):2061. https://doi.org/10.3390/ijms21062061
Yan F, Dai G, Zheng X (2016) Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/db mice. J Nutr Biochem 36:68–80. https://doi.org/10.1016/j.jnutbio.2016.07.004
You M, Arteel GE (2019) Effect of ethanol on lipid metabolism. J Hepatol 70(2):237–248. https://doi.org/10.1016/j.jhep.2018.10.037
Yuan K, Zhang X, Lv L, Zhang J, Liang W, Wang P (2016) Fine-tuning the expression of microRNA-155 controls acetaminophen-induced liver inflammation. Int Immunopharmacol 40:339–346. https://doi.org/10.1016/j.intimp.2016.09.011
Yuan Q, Zhao L (2017) The Mulberry (Morus alba L.) Fruit-a review of characteristic components and health benefits. J Agric Food Chem 65(48):10383–10394. https://doi.org/10.1021/acs.jafc.7b03614
Zhang BH, Pan XP, Cobb GP, Anderson TA (2007) MicroRNAs as oncogenes and tumor suppressor genes. Dev Biol 302(1):1–12. https://doi.org/10.1016/j.ydbio
Zhou XJ, Zhu CT, Zhang LY, You S, Wu FA, Wang J (2021) Enrichment and purification of red pigments from defective mulberry fruits using biotransformation in a liquid-liquid-solid three-phase system. Environ Sci Pollut Res Int 28(19):24432–24440. https://doi.org/10.1007/s11356-020-08731-2
Funding
This study was supported by grants from National international cooperation base of China (Guoke Foreign Letter (2016) No. 65), the Scientific Research Project of “Double First-class” Chinese Medicine in Henan Province (HSRP-DFCTCM-2023-7-25) and the key scientific research projects of universities in Henan Province (21A360022).
Author information
Authors and Affiliations
Contributions
Conceptualization, JQ, MM; methodology, JQ, HL; validation, JC, YS; formal analysis, NL, PZ; writing-original draft preparation, JQ, HL; writing—review and editing, PZ and SZ; supervision, MM.
Corresponding author
Ethics declarations
Ethics approval
All animal experiments complied with the National Research Council’s Guide for the Care and Use of Laboratory Animals. This study was approved by the Animal Welfare Ethics Committee of Henan University of Chinese Medicine (DWLL202003219).
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Qiao, J., Li, H., Jinxiang, C. et al. Mulberry fruit repairs alcoholic liver injury by modulating lipid metabolism and the expression of miR-155 and PPARα in rats. Funct Integr Genomics 23, 261 (2023). https://doi.org/10.1007/s10142-023-01131-y
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10142-023-01131-y