SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy
Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomit...
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| Veröffentlicht in: | Scientific reports 2016-10, Vol.6 (1), p.35732-35732, Article 35732 |
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| creator | Kim, Kwang-Youn Jang, Hyun-Jun Yang, Yong Ryoul Park, Kwang-Il Seo, JeongKon Shin, Il-Woo Jeon, Tae-Il Ahn, Soon-cheol Suh, Pann-Ghill Osborne, Timothy F. Seo, Young-Kyo |
| description | Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients. |
| doi_str_mv | 10.1038/srep35732 |
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Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep35732</identifier><identifier>PMID: 27767079</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/109 ; 38 ; 38/15 ; 631/337/572/2102 ; 631/443/319/1642/2815 ; 64 ; 64/60 ; Animals ; Anticholesteremic Agents - administration & dosage ; Autophagosomes - metabolism ; Autophagy ; Autophagy - drug effects ; Autophagy - physiology ; Cells, Cultured ; Diet, High-Fat - adverse effects ; Disease Models, Animal ; Drug Therapy, Combination ; Ezetimibe - administration & dosage ; Fatty liver ; Group VI Phospholipases A2 - metabolism ; Hepatocytes ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Hepatocytes - pathology ; High fat diet ; Homeostasis ; Humanities and Social Sciences ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage ; Liver diseases ; Lovastatin ; Lovastatin - administration & dosage ; Male ; Mice ; Mice, Inbred C57BL ; multidisciplinary ; Non-alcoholic Fatty Liver Disease - drug therapy ; Non-alcoholic Fatty Liver Disease - metabolism ; Non-alcoholic Fatty Liver Disease - pathology ; Overexpression ; Phagocytosis ; Phagosomes ; Phospholipase ; Rodents ; Science ; Signal Transduction - drug effects ; Statins ; Steatosis ; Sterol Regulatory Element Binding Protein 2 - metabolism ; Sterol regulatory element-binding protein ; Triglycerides - metabolism</subject><ispartof>Scientific reports, 2016-10, Vol.6 (1), p.35732-35732, Article 35732</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Oct 2016</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-3453f0bf1a437ab0c52e786d366662d819e8c61a80562658fe531c8f11ca10883</citedby><cites>FETCH-LOGICAL-c438t-3453f0bf1a437ab0c52e786d366662d819e8c61a80562658fe531c8f11ca10883</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/PMC5073315/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073315/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27767079$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Kwang-Youn</creatorcontrib><creatorcontrib>Jang, Hyun-Jun</creatorcontrib><creatorcontrib>Yang, Yong Ryoul</creatorcontrib><creatorcontrib>Park, Kwang-Il</creatorcontrib><creatorcontrib>Seo, JeongKon</creatorcontrib><creatorcontrib>Shin, Il-Woo</creatorcontrib><creatorcontrib>Jeon, Tae-Il</creatorcontrib><creatorcontrib>Ahn, Soon-cheol</creatorcontrib><creatorcontrib>Suh, Pann-Ghill</creatorcontrib><creatorcontrib>Osborne, Timothy F.</creatorcontrib><creatorcontrib>Seo, Young-Kyo</creatorcontrib><title>SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.</description><subject>13</subject><subject>13/1</subject><subject>13/109</subject><subject>38</subject><subject>38/15</subject><subject>631/337/572/2102</subject><subject>631/443/319/1642/2815</subject><subject>64</subject><subject>64/60</subject><subject>Animals</subject><subject>Anticholesteremic Agents - administration & dosage</subject><subject>Autophagosomes - metabolism</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Autophagy - physiology</subject><subject>Cells, Cultured</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Disease Models, Animal</subject><subject>Drug Therapy, Combination</subject><subject>Ezetimibe - administration & dosage</subject><subject>Fatty liver</subject><subject>Group VI Phospholipases A2 - metabolism</subject><subject>Hepatocytes</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - pathology</subject><subject>High fat diet</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</subject><subject>Liver diseases</subject><subject>Lovastatin</subject><subject>Lovastatin - administration & dosage</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>multidisciplinary</subject><subject>Non-alcoholic Fatty Liver Disease - drug therapy</subject><subject>Non-alcoholic Fatty Liver Disease - metabolism</subject><subject>Non-alcoholic Fatty Liver Disease - pathology</subject><subject>Overexpression</subject><subject>Phagocytosis</subject><subject>Phagosomes</subject><subject>Phospholipase</subject><subject>Rodents</subject><subject>Science</subject><subject>Signal Transduction - drug effects</subject><subject>Statins</subject><subject>Steatosis</subject><subject>Sterol Regulatory Element Binding Protein 2 - metabolism</subject><subject>Sterol regulatory element-binding protein</subject><subject>Triglycerides - metabolism</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNplkVtrGzEQhUVJaUKSh_6BIMhLGthEl9Wu9qXgBOcCJjW9vFaMZa1XYb3aSFpT__vIODVuMy8zMB9nznAQ-kzJFSVcXgdvei5Kzj6gI0ZykTHO2MHefIhOQ3gmqQSrclp9QoesLIuSlNUR-v3j-_hmmrHr6dN0MpIY_tiA7bL3bmUC7lyXQatd41qrcQ0xrnFrV8bjuQ0GgsGx8W5YNBh0tCuI1nXY1RiG6PoGFusT9LGGNpjTt36Mft2Nf94-ZJNv94-3o0mmcy5jxnPBazKrKeS8hBnRgplSFnNepGJzSSsjdUFBElGwQsjaCE61rCnVQImU_Bh93er2w2xp5tp00UOrem-X4NfKgVX_bjrbqIVbKUFKzqlIAhdvAt69DCZEtbRBm7aFzrghKCq5ELTIZZXQ8__QZzf4Lr2XqKqijPBi4-jLltLehZRRvTNDidoEp3bBJfZs3_2O_BtTAi63QEirbmH83sl3aq_JxKE-</recordid><startdate>20161021</startdate><enddate>20161021</enddate><creator>Kim, Kwang-Youn</creator><creator>Jang, Hyun-Jun</creator><creator>Yang, Yong Ryoul</creator><creator>Park, Kwang-Il</creator><creator>Seo, JeongKon</creator><creator>Shin, Il-Woo</creator><creator>Jeon, Tae-Il</creator><creator>Ahn, Soon-cheol</creator><creator>Suh, Pann-Ghill</creator><creator>Osborne, Timothy F.</creator><creator>Seo, Young-Kyo</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161021</creationdate><title>SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy</title><author>Kim, Kwang-Youn ; Jang, Hyun-Jun ; Yang, Yong Ryoul ; Park, Kwang-Il ; Seo, JeongKon ; Shin, Il-Woo ; Jeon, Tae-Il ; Ahn, Soon-cheol ; Suh, Pann-Ghill ; Osborne, Timothy F. ; Seo, Young-Kyo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-3453f0bf1a437ab0c52e786d366662d819e8c61a80562658fe531c8f11ca10883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13</topic><topic>13/1</topic><topic>13/109</topic><topic>38</topic><topic>38/15</topic><topic>631/337/572/2102</topic><topic>631/443/319/1642/2815</topic><topic>64</topic><topic>64/60</topic><topic>Animals</topic><topic>Anticholesteremic Agents - 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drug therapy</topic><topic>Non-alcoholic Fatty Liver Disease - metabolism</topic><topic>Non-alcoholic Fatty Liver Disease - pathology</topic><topic>Overexpression</topic><topic>Phagocytosis</topic><topic>Phagosomes</topic><topic>Phospholipase</topic><topic>Rodents</topic><topic>Science</topic><topic>Signal Transduction - drug effects</topic><topic>Statins</topic><topic>Steatosis</topic><topic>Sterol Regulatory Element Binding Protein 2 - metabolism</topic><topic>Sterol regulatory element-binding protein</topic><topic>Triglycerides - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Kwang-Youn</creatorcontrib><creatorcontrib>Jang, Hyun-Jun</creatorcontrib><creatorcontrib>Yang, Yong Ryoul</creatorcontrib><creatorcontrib>Park, Kwang-Il</creatorcontrib><creatorcontrib>Seo, JeongKon</creatorcontrib><creatorcontrib>Shin, Il-Woo</creatorcontrib><creatorcontrib>Jeon, Tae-Il</creatorcontrib><creatorcontrib>Ahn, Soon-cheol</creatorcontrib><creatorcontrib>Suh, Pann-Ghill</creatorcontrib><creatorcontrib>Osborne, Timothy F.</creatorcontrib><creatorcontrib>Seo, Young-Kyo</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>MEDLINE - Academic</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>Kim, Kwang-Youn</au><au>Jang, Hyun-Jun</au><au>Yang, Yong Ryoul</au><au>Park, Kwang-Il</au><au>Seo, JeongKon</au><au>Shin, Il-Woo</au><au>Jeon, Tae-Il</au><au>Ahn, Soon-cheol</au><au>Suh, Pann-Ghill</au><au>Osborne, Timothy F.</au><au>Seo, Young-Kyo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-10-21</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>35732</spage><epage>35732</epage><pages>35732-35732</pages><artnum>35732</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27767079</pmid><doi>10.1038/srep35732</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/1 13/109 38 38/15 631/337/572/2102 631/443/319/1642/2815 64 64/60 Animals Anticholesteremic Agents - administration & dosage Autophagosomes - metabolism Autophagy Autophagy - drug effects Autophagy - physiology Cells, Cultured Diet, High-Fat - adverse effects Disease Models, Animal Drug Therapy, Combination Ezetimibe - administration & dosage Fatty liver Group VI Phospholipases A2 - metabolism Hepatocytes Hepatocytes - drug effects Hepatocytes - metabolism Hepatocytes - pathology High fat diet Homeostasis Humanities and Social Sciences Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage Liver diseases Lovastatin Lovastatin - administration & dosage Male Mice Mice, Inbred C57BL multidisciplinary Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - metabolism Non-alcoholic Fatty Liver Disease - pathology Overexpression Phagocytosis Phagosomes Phospholipase Rodents Science Signal Transduction - drug effects Statins Steatosis Sterol Regulatory Element Binding Protein 2 - metabolism Sterol regulatory element-binding protein Triglycerides - metabolism |
| title | SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy |
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