Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis
Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we eval...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2022-04, Vol.43 (4), p.941-953 |
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| creator | Huang, He-ming Fan, Shi-jie Zhou, Xiao-ru Liu, Yan-jun Li, Xiao Liao, Li-ping Huang, Jing Shi, Cui-cui Yu, Liang Fu, Rong Fan, Jian-gao Zhang, Yuan-yuan Luo, Cheng Li, Guang-ming |
| description | Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg
−1
·d
−1
, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH. |
| doi_str_mv | 10.1038/s41401-021-00725-1 |
| format | Article |
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−1
·d
−1
, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-021-00725-1</identifier><identifier>PMID: 34341511</identifier><language>eng</language><publisher>Singapore: Springer Singapore</publisher><subject>Animals ; Biomedical and Life Sciences ; Biomedicine ; Carbamates ; Cholesterol ; Fatty liver ; Fetuses ; Fibrosis ; Hepatocellular carcinoma ; Histone deacetylase ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylase Inhibitors - therapeutic use ; Immunology ; Inflammation ; Internal Medicine ; Lipid metabolism ; Liver ; Liver - metabolism ; Liver cancer ; Liver Cirrhosis - pathology ; Liver diseases ; Medical Microbiology ; Methionine ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease - metabolism ; Nutrient deficiency ; Palmitic acid ; Pharmacology/Toxicology ; Steatosis ; Vaccine</subject><ispartof>Acta pharmacologica Sinica, 2022-04, Vol.43 (4), p.941-953</ispartof><rights>The Author(s), under exclusive licence to CPS and SIMM 2021</rights><rights>2021. The Author(s), under exclusive licence to CPS and SIMM.</rights><rights>The Author(s), under exclusive licence to CPS and SIMM 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-945b55b5452bb3c21aeb1907f7748698132027de5b71fdee486c8a72531990193</citedby><cites>FETCH-LOGICAL-c474t-945b55b5452bb3c21aeb1907f7748698132027de5b71fdee486c8a72531990193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975805/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975805/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34341511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, He-ming</creatorcontrib><creatorcontrib>Fan, Shi-jie</creatorcontrib><creatorcontrib>Zhou, Xiao-ru</creatorcontrib><creatorcontrib>Liu, Yan-jun</creatorcontrib><creatorcontrib>Li, Xiao</creatorcontrib><creatorcontrib>Liao, Li-ping</creatorcontrib><creatorcontrib>Huang, Jing</creatorcontrib><creatorcontrib>Shi, Cui-cui</creatorcontrib><creatorcontrib>Yu, Liang</creatorcontrib><creatorcontrib>Fu, Rong</creatorcontrib><creatorcontrib>Fan, Jian-gao</creatorcontrib><creatorcontrib>Zhang, Yuan-yuan</creatorcontrib><creatorcontrib>Luo, Cheng</creatorcontrib><creatorcontrib>Li, Guang-ming</creatorcontrib><title>Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg
−1
·d
−1
, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.</description><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Carbamates</subject><subject>Cholesterol</subject><subject>Fatty liver</subject><subject>Fetuses</subject><subject>Fibrosis</subject><subject>Hepatocellular carcinoma</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylase Inhibitors - therapeutic use</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Internal Medicine</subject><subject>Lipid metabolism</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver cancer</subject><subject>Liver Cirrhosis - pathology</subject><subject>Liver diseases</subject><subject>Medical Microbiology</subject><subject>Methionine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Non-alcoholic Fatty Liver Disease - metabolism</subject><subject>Nutrient deficiency</subject><subject>Palmitic acid</subject><subject>Pharmacology/Toxicology</subject><subject>Steatosis</subject><subject>Vaccine</subject><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU1v1DAQhi0EoqXwBzggS1x6CXj8ESeXSlVVKFIlLnC2HGey6yprL7az0v77etlSaA9Itvwxz7z2zEvIe2CfgInuc5YgGTSM18k0Vw28IKegpWrqQb6s-1ZDI1knTsibnO8YE1xA_5qcCCkkKIBT4m58LjEgHdE6LPvZZqQ-rP3gS0x05Xc-xFxsobYUDIstmGmIwc4uruPsHc0FbYlr3Nrii8_UhpHOfoeJTn5IMfv8lrya7Jzx3cN6Rn5-uf5xddPcfv_67erytnFSy9L0Ug2qDqn4MAjHweIAPdOT1rJr-w4EZ1yPqAYN04hYL11na6m1pp5BL87IxVF3uwwbHB2GkuxstslvbNqbaL15Ggl-bVZxZ7peq46pKnD-IJDirwVzMRufHc6zDRiXbLhSWimmNFT04zP0Li6ptqVSrWwZtAAHQX6kXG1ETjg9fgaYOXhojh6a6qH57aE5SH_4t4zHlD-mVUAcgVxDYYXp79v_kb0HUT6pHQ</recordid><startdate>20220401</startdate><enddate>20220401</enddate><creator>Huang, He-ming</creator><creator>Fan, Shi-jie</creator><creator>Zhou, Xiao-ru</creator><creator>Liu, Yan-jun</creator><creator>Li, Xiao</creator><creator>Liao, Li-ping</creator><creator>Huang, Jing</creator><creator>Shi, Cui-cui</creator><creator>Yu, Liang</creator><creator>Fu, Rong</creator><creator>Fan, Jian-gao</creator><creator>Zhang, Yuan-yuan</creator><creator>Luo, Cheng</creator><creator>Li, Guang-ming</creator><general>Springer Singapore</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20220401</creationdate><title>Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis</title><author>Huang, He-ming ; Fan, Shi-jie ; Zhou, Xiao-ru ; Liu, Yan-jun ; Li, Xiao ; Liao, Li-ping ; Huang, Jing ; Shi, Cui-cui ; Yu, Liang ; Fu, Rong ; Fan, Jian-gao ; Zhang, Yuan-yuan ; Luo, Cheng ; Li, Guang-ming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-945b55b5452bb3c21aeb1907f7748698132027de5b71fdee486c8a72531990193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Carbamates</topic><topic>Cholesterol</topic><topic>Fatty liver</topic><topic>Fetuses</topic><topic>Fibrosis</topic><topic>Hepatocellular carcinoma</topic><topic>Histone deacetylase</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylase Inhibitors - therapeutic use</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Internal Medicine</topic><topic>Lipid metabolism</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver cancer</topic><topic>Liver Cirrhosis - pathology</topic><topic>Liver diseases</topic><topic>Medical Microbiology</topic><topic>Methionine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Non-alcoholic Fatty Liver Disease - metabolism</topic><topic>Nutrient deficiency</topic><topic>Palmitic acid</topic><topic>Pharmacology/Toxicology</topic><topic>Steatosis</topic><topic>Vaccine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, He-ming</creatorcontrib><creatorcontrib>Fan, Shi-jie</creatorcontrib><creatorcontrib>Zhou, Xiao-ru</creatorcontrib><creatorcontrib>Liu, Yan-jun</creatorcontrib><creatorcontrib>Li, Xiao</creatorcontrib><creatorcontrib>Liao, Li-ping</creatorcontrib><creatorcontrib>Huang, Jing</creatorcontrib><creatorcontrib>Shi, Cui-cui</creatorcontrib><creatorcontrib>Yu, Liang</creatorcontrib><creatorcontrib>Fu, Rong</creatorcontrib><creatorcontrib>Fan, Jian-gao</creatorcontrib><creatorcontrib>Zhang, Yuan-yuan</creatorcontrib><creatorcontrib>Luo, Cheng</creatorcontrib><creatorcontrib>Li, Guang-ming</creatorcontrib><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>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</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 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>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</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>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</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 China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, He-ming</au><au>Fan, Shi-jie</au><au>Zhou, Xiao-ru</au><au>Liu, Yan-jun</au><au>Li, Xiao</au><au>Liao, Li-ping</au><au>Huang, Jing</au><au>Shi, Cui-cui</au><au>Yu, Liang</au><au>Fu, Rong</au><au>Fan, Jian-gao</au><au>Zhang, Yuan-yuan</au><au>Luo, Cheng</au><au>Li, Guang-ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2022-04-01</date><risdate>2022</risdate><volume>43</volume><issue>4</issue><spage>941</spage><epage>953</epage><pages>941-953</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg
−1
·d
−1
, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.</abstract><cop>Singapore</cop><pub>Springer Singapore</pub><pmid>34341511</pmid><doi>10.1038/s41401-021-00725-1</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta pharmacologica Sinica, 2022-04, Vol.43 (4), p.941-953 |
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| source | MEDLINE; PubMed Central; Alma/SFX Local Collection |
| subjects | Animals Biomedical and Life Sciences Biomedicine Carbamates Cholesterol Fatty liver Fetuses Fibrosis Hepatocellular carcinoma Histone deacetylase Histone Deacetylase Inhibitors - pharmacology Histone Deacetylase Inhibitors - therapeutic use Immunology Inflammation Internal Medicine Lipid metabolism Liver Liver - metabolism Liver cancer Liver Cirrhosis - pathology Liver diseases Medical Microbiology Methionine Mice Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease - metabolism Nutrient deficiency Palmitic acid Pharmacology/Toxicology Steatosis Vaccine |
| title | Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis |
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