Dasatinib and Quercetin As Senolytic Drugs Improve Fat Deposition and Exhibit Antifibrotic Effects in the Medaka Metabolic Dysfunction-Associated Steatotic Liver Disease Model

Overview

Journal Diseases

Date 2024 Dec 27

PMID 39727647

Authors

Shunta Yakubo

Hiroyuki Abe

Yawen Li

Marina Kudo

Atsushi Kimura

Takuya Wakabayashi

Yusuke Watanabe

Naruhiro Kimura

Toru Setsu

Takeshi Yokoo

Akira Sakamaki

Hiroteru Kamimura

Atsunori Tsuchiya

Kenya Kamimura

Shuji Terai

Affiliations

Soon will be listed here.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) causes cellular senescence due to oxidative stress, endoplasmic reticulum stress, and ectopic fat deposition in the liver. Recently, dasatinib, an antitumor agent, and quercetin, a dietary supplement, were combined as a senolytic drug to eliminate senescent cells. Thus, this study aimed to examine the effects of dasatinib and quercetin administration on removing senescent cells and their therapeutic effects on MASLD in a medaka MASLD model. Dasatinib and quercetin were administered to a medaka MASLD model, which was fed a high-fat diet by dissolving them in aquarium water. The results revealed that senescent cells in the liver were increased in the HFD group but improved in the treatment group. Hematoxylin and eosin staining also showed that treatment improved fat deposition in hepatocytes. In addition, TGFβ1, a driver factor of fibrosis, was reduced in the treatment group. Dasatinib and quercetin eliminated senescent cells in MASLD, attenuated fat deposition, and suppressed fibrosis gene expression. The results indicate that dasatinib and quercetin as senolytic drugs are novel therapeutic agents that reduce MASLD.

References

Shinagawa-Kobayashi Y, Kamimura K, Goto R, Ogawa K, Inoue R, Yokoo T . Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model. Biochem Biophys Res Commun. 2018; 496(2):556-561. DOI: 10.1016/j.bbrc.2018.01.057. View

Coppe J, Desprez P, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. PMC: 4166495. DOI: 10.1146/annurev-pathol-121808-102144. View

Kobori M, Masumoto S, Akimoto Y, Oike H . Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a Western-style diet in C57/BL6J mice. Mol Nutr Food Res. 2011; 55(4):530-40. DOI: 10.1002/mnfr.201000392. View

Omori S, Wang T, Johmura Y, Kanai T, Nakano Y, Kido T . Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16 Cells In Vivo. Cell Metab. 2020; 32(5):814-828.e6. DOI: 10.1016/j.cmet.2020.09.006. View

Younossi Z, Koenig A, Abdelatif D, Fazel Y, Henry L, Wymer M . Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2015; 64(1):73-84. DOI: 10.1002/hep.28431. View

Suda M, Paul K, Minamino T, Miller J, Lerman A, Ellison-Hughes G . Senescent Cells: A Therapeutic Target in Cardiovascular Diseases. Cells. 2023; 12(9). PMC: 10177324. DOI: 10.3390/cells12091296. View

Itoh M, Tamura A, Kanai S, Tanaka M, Kanamori Y, Shirakawa I . Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH. J Exp Med. 2023; 220(11). PMC: 10506914. DOI: 10.1084/jem.20220681. View

Zhu Y, Tchkonia T, Pirtskhalava T, Gower A, Ding H, Giorgadze N . The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015; 14(4):644-58. PMC: 4531078. DOI: 10.1111/acel.12344. View

Kimura A, Kamimura K, Ohkoshi-Yamada M, Shinagawa-Kobayashi Y, Goto R, Owaki T . Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model. Biochem Biophys Res Commun. 2022; 596:76-82. DOI: 10.1016/j.bbrc.2022.01.086. View

10.

Qi R, Jiang R, Xiao H, Wang Z, He S, Wang L . Ginsenoside Rg1 protects against d-galactose induced fatty liver disease in a mouse model via FOXO1 transcriptional factor. Life Sci. 2020; 254:117776. DOI: 10.1016/j.lfs.2020.117776. View

11.

Mantadaki A, Baliou S, Linardakis M, Vakonaki E, Tzatzarakis M, Tsatsakis A . Quercetin Intake and Absolute Telomere Length in Patients with Type 2 Diabetes Mellitus: Novel Findings from a Randomized Controlled Before-and-After Study. Pharmaceuticals (Basel). 2024; 17(9). PMC: 11434860. DOI: 10.3390/ph17091136. View

12.

Lagnado A, Leslie J, Ruchaud-Sparagano M, Victorelli S, Hirsova P, Ogrodnik M . Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 2021; 40(9):e106048. PMC: 8090854. DOI: 10.15252/embj.2020106048. View

13.

Goto R, Kamimura K, Shinagawa-Kobayashi Y, Sakai N, Nagoya T, Niwa Y . Inhibition of sodium glucose cotransporter 2 (SGLT2) delays liver fibrosis in a medaka model of nonalcoholic steatohepatitis (NASH). FEBS Open Bio. 2019; 9(4):643-652. PMC: 6443870. DOI: 10.1002/2211-5463.12598. View

14.

Ohkoshi-Yamada M, Kamimura K, Kimura A, Tanaka Y, Nagayama I, Yakubo S . Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model. Biochem Biophys Res Commun. 2022; 625:116-121. DOI: 10.1016/j.bbrc.2022.07.117. View

15.

Weber L, Kiparissis Y, Hwang G, Niimi A, Janz D, Metcalfe C . Increased cellular apoptosis after chronic aqueous exposure to nonylphenol and quercetin in adult medaka (Oryzias latipes). Comp Biochem Physiol C Toxicol Pharmacol. 2002; 131(1):51-9. DOI: 10.1016/s1532-0456(01)00276-9. View

16.

Kuwashiro S, Terai S, Oishi T, Fujisawa K, Matsumoto T, Nishina H . Telmisartan improves nonalcoholic steatohepatitis in medaka (Oryzias latipes) by reducing macrophage infiltration and fat accumulation. Cell Tissue Res. 2011; 344(1):125-34. PMC: 3063342. DOI: 10.1007/s00441-011-1132-7. View

17.

Ishizuka K, Kon K, Lee-Okada H, Arai K, Uchiyama A, Yamashina S . Aging exacerbates high-fat diet-induced steatohepatitis through alteration in hepatic lipid metabolism in mice. J Gastroenterol Hepatol. 2020; 35(8):1437-1448. DOI: 10.1111/jgh.15006. View

18.

Takaya K, Kishi K . Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo. Biogerontology. 2024; 25(4):691-704. DOI: 10.1007/s10522-024-10103-z. View

19.

Sasako T, Ohsugi M, Kubota N, Itoh S, Okazaki Y, Terai A . Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism. Nat Commun. 2019; 10(1):947. PMC: 6393527. DOI: 10.1038/s41467-019-08591-6. View

20.

Tanaka S, Hikita H, Tatsumi T, Sakamori R, Nozaki Y, Sakane S . Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology. 2016; 64(6):1994-2014. DOI: 10.1002/hep.28820. View