Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice
Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whet...
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| Veröffentlicht in: | Scientific reports 2020-01, Vol.10 (1), p.815, Article 815 |
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| creator | Nishikawa, Tomoki Nagata, Naoto Shimakami, Tetsuro Shirakura, Takashi Matsui, Chieko Ni, Yinhua Zhuge, Fen Xu, Liang Chen, Guanliang Nagashimada, Mayumi Yamashita, Taro Sakai, Yoshio Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Kaneko, Shuichi Ota, Tsuguhito |
| description | Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia. |
| doi_str_mv | 10.1038/s41598-020-57784-3 |
| format | Article |
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Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-57784-3</identifier><identifier>PMID: 31965018</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 38/77 ; 64/60 ; 692/163/2743/2037 ; 692/4020/4021/1607/2750 ; 82/80 ; Alanine ; Alanine transaminase ; Allopurinol ; Allopurinol - pharmacology ; Allopurinol - therapeutic use ; Animal models ; Animals ; Aspartate aminotransferase ; Diet ; Diet, High-Fat - adverse effects ; Disease Models, Animal ; Fatty liver ; Fatty Liver - drug therapy ; Fatty Liver - etiology ; Fatty Liver - metabolism ; Febuxostat - pharmacology ; Febuxostat - therapeutic use ; Fibrosis ; Gout ; Humanities and Social Sciences ; Hyperuricemia ; Hyperuricemia - drug therapy ; Hyperuricemia - etiology ; Insulin ; Insulin Resistance ; Lipid peroxidation ; Lipid Peroxidation - drug effects ; Liver ; Liver - enzymology ; Liver diseases ; Macrophage Activation - drug effects ; Macrophages ; Mice, Inbred C57BL ; Molecular Targeted Therapy ; multidisciplinary ; Peroxidation ; Science ; Science (multidisciplinary) ; Serum levels ; Steatosis ; Therapeutic applications ; Uric acid ; Uric Acid - metabolism ; Xanthine oxidase ; Xanthine Oxidase - antagonists & inhibitors</subject><ispartof>Scientific reports, 2020-01, Vol.10 (1), p.815, Article 815</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-8592d7d78b1cd7b428c95cd971c26a88e77898f8c6556b104e661871fe918e813</citedby><cites>FETCH-LOGICAL-c540t-8592d7d78b1cd7b428c95cd971c26a88e77898f8c6556b104e661871fe918e813</cites><orcidid>0000-0002-2389-2334 ; 0000-0002-2216-8459</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972756/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972756/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31965018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nishikawa, Tomoki</creatorcontrib><creatorcontrib>Nagata, Naoto</creatorcontrib><creatorcontrib>Shimakami, Tetsuro</creatorcontrib><creatorcontrib>Shirakura, Takashi</creatorcontrib><creatorcontrib>Matsui, Chieko</creatorcontrib><creatorcontrib>Ni, Yinhua</creatorcontrib><creatorcontrib>Zhuge, Fen</creatorcontrib><creatorcontrib>Xu, Liang</creatorcontrib><creatorcontrib>Chen, Guanliang</creatorcontrib><creatorcontrib>Nagashimada, Mayumi</creatorcontrib><creatorcontrib>Yamashita, Taro</creatorcontrib><creatorcontrib>Sakai, Yoshio</creatorcontrib><creatorcontrib>Yamashita, Tatsuya</creatorcontrib><creatorcontrib>Mizukoshi, Eishiro</creatorcontrib><creatorcontrib>Honda, Masao</creatorcontrib><creatorcontrib>Kaneko, Shuichi</creatorcontrib><creatorcontrib>Ota, Tsuguhito</creatorcontrib><title>Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.</description><subject>13/31</subject><subject>38/77</subject><subject>64/60</subject><subject>692/163/2743/2037</subject><subject>692/4020/4021/1607/2750</subject><subject>82/80</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Allopurinol</subject><subject>Allopurinol - pharmacology</subject><subject>Allopurinol - therapeutic use</subject><subject>Animal models</subject><subject>Animals</subject><subject>Aspartate aminotransferase</subject><subject>Diet</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Disease Models, Animal</subject><subject>Fatty liver</subject><subject>Fatty Liver - drug therapy</subject><subject>Fatty Liver - etiology</subject><subject>Fatty Liver - metabolism</subject><subject>Febuxostat - pharmacology</subject><subject>Febuxostat - therapeutic use</subject><subject>Fibrosis</subject><subject>Gout</subject><subject>Humanities and Social Sciences</subject><subject>Hyperuricemia</subject><subject>Hyperuricemia - 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metabolism</topic><topic>Xanthine oxidase</topic><topic>Xanthine Oxidase - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nishikawa, Tomoki</creatorcontrib><creatorcontrib>Nagata, Naoto</creatorcontrib><creatorcontrib>Shimakami, Tetsuro</creatorcontrib><creatorcontrib>Shirakura, Takashi</creatorcontrib><creatorcontrib>Matsui, Chieko</creatorcontrib><creatorcontrib>Ni, Yinhua</creatorcontrib><creatorcontrib>Zhuge, Fen</creatorcontrib><creatorcontrib>Xu, Liang</creatorcontrib><creatorcontrib>Chen, Guanliang</creatorcontrib><creatorcontrib>Nagashimada, Mayumi</creatorcontrib><creatorcontrib>Yamashita, Taro</creatorcontrib><creatorcontrib>Sakai, Yoshio</creatorcontrib><creatorcontrib>Yamashita, Tatsuya</creatorcontrib><creatorcontrib>Mizukoshi, Eishiro</creatorcontrib><creatorcontrib>Honda, Masao</creatorcontrib><creatorcontrib>Kaneko, Shuichi</creatorcontrib><creatorcontrib>Ota, Tsuguhito</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nishikawa, Tomoki</au><au>Nagata, Naoto</au><au>Shimakami, Tetsuro</au><au>Shirakura, Takashi</au><au>Matsui, Chieko</au><au>Ni, Yinhua</au><au>Zhuge, Fen</au><au>Xu, Liang</au><au>Chen, Guanliang</au><au>Nagashimada, Mayumi</au><au>Yamashita, Taro</au><au>Sakai, Yoshio</au><au>Yamashita, Tatsuya</au><au>Mizukoshi, Eishiro</au><au>Honda, Masao</au><au>Kaneko, Shuichi</au><au>Ota, Tsuguhito</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-01-21</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>815</spage><pages>815-</pages><artnum>815</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31965018</pmid><doi>10.1038/s41598-020-57784-3</doi><orcidid>https://orcid.org/0000-0002-2389-2334</orcidid><orcidid>https://orcid.org/0000-0002-2216-8459</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/31 38/77 64/60 692/163/2743/2037 692/4020/4021/1607/2750 82/80 Alanine Alanine transaminase Allopurinol Allopurinol - pharmacology Allopurinol - therapeutic use Animal models Animals Aspartate aminotransferase Diet Diet, High-Fat - adverse effects Disease Models, Animal Fatty liver Fatty Liver - drug therapy Fatty Liver - etiology Fatty Liver - metabolism Febuxostat - pharmacology Febuxostat - therapeutic use Fibrosis Gout Humanities and Social Sciences Hyperuricemia Hyperuricemia - drug therapy Hyperuricemia - etiology Insulin Insulin Resistance Lipid peroxidation Lipid Peroxidation - drug effects Liver Liver - enzymology Liver diseases Macrophage Activation - drug effects Macrophages Mice, Inbred C57BL Molecular Targeted Therapy multidisciplinary Peroxidation Science Science (multidisciplinary) Serum levels Steatosis Therapeutic applications Uric acid Uric Acid - metabolism Xanthine oxidase Xanthine Oxidase - antagonists & inhibitors |
| title | Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T03%3A48%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Xanthine%20oxidase%20inhibition%20attenuates%20insulin%20resistance%20and%20diet-induced%20steatohepatitis%20in%20mice&rft.jtitle=Scientific%20reports&rft.au=Nishikawa,%20Tomoki&rft.date=2020-01-21&rft.volume=10&rft.issue=1&rft.spage=815&rft.pages=815-&rft.artnum=815&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-020-57784-3&rft_dat=%3Cproquest_pubme%3E2343027493%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2343027493&rft_id=info:pmid/31965018&rfr_iscdi=true |