{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:08:25Z","timestamp":1791216505030,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2023,11]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Accumulation of lipid in the liver is the first hallmark of both alcohol\u2010related liver disease (ALD) and non\u2010alcohol\u2010related fatty liver disease (NAFLD). Recent studies indicate that specific mutations in lipid genes confer risk and might influence disease progression to irreversible liver cirrhosis. This study aimed to understand the function\/s of lipid risk genes driving disease development in zebrafish genetic models of alcohol\u2010related and non\u2010alcohol\u2010related fatty liver.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We used zebrafish larvae to investigate the effect of alcohol and high fat to model fatty liver and tested the utility of this model to study lipid risk gene functions. CRISPR\/Cas9 gene editing was used to create knockdowns in 5\u2009days post\u2010fertilisation zebrafish larvae for the available orthologs of human cirrhosis risk genes (\n pnpla3<\/jats:italic>\n ,\n faf2<\/jats:italic>\n ,\n tm6sf2<\/jats:italic>\n ). To establish fatty liver models, larvae were exposed to ethanol and a high\u2010fat diet (HFD) consisting of chicken egg yolk. Changes in morphology (imaging), survival, liver injury (biochemical tests, histopathology), gene expression (qPCR) and lipid accumulation (dye\u2010specific live imaging) were analysed across treatment groups to test the functions of these genes.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Exposure of 5\u2010day post\u2010fertilisation (dpf) WT larvae to 2% ethanol or HFD for 48\u2009h developed measurable hepatic steatosis. CRISPR\u2010Cas9 genome editing depleted\n pnpla3<\/jats:italic>\n ,\n faf2<\/jats:italic>\n and\n tm6sf2<\/jats:italic>\n gene expression in these CRISPR knockdown larvae (crispants). Depletion significantly increased the effects of ethanol and HFD toxicity by increasing hepatic steatosis and hepatic neutrophil recruitment \u22652\u2010fold in all three crispants. Furthermore, ethanol or HFD exposure significantly altered the expression of genes associated with ethanol metabolism (\n cyp2y3<\/jats:italic>\n ) and lipid metabolism\u2010related gene expression, including\n atgl<\/jats:italic>\n (triglyceride hydrolysis),\n axox1<\/jats:italic>\n ,\n echs1<\/jats:italic>\n (fatty acid \u03b2\u2010oxidation),\n fabp10a<\/jats:italic>\n (transport),\n hmgcra<\/jats:italic>\n (metabolism),\n notch1<\/jats:italic>\n (signalling) and\n srebp1<\/jats:italic>\n (lipid synthesis), in all three\n pnpla3<\/jats:italic>\n ,\n faf2<\/jats:italic>\n and\n tm6sf2<\/jats:italic>\n crispants. Nile Red staining in all three crispants revealed significantly increased lipid droplet size and triglyceride accumulation in the livers following exposure to ethanol or HFD.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n We identified roles for\n pnpla3<\/jats:italic>\n ,\n faf2<\/jats:italic>\n and\n tm6sf2<\/jats:italic>\n genes in triglyceride accumulation and fatty acid oxidation pathways in a zebrafish larvae model of fatty liver.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/liv.15716","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T04:21:33Z","timestamp":1693455693000},"page":"2455-2468","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Investigating the role of lipid genes in liver disease using fatty liver models of alcohol and high fat in zebrafish (\n Danio rerio<\/i>\n )"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6362-1221","authenticated-orcid":false,"given":"Fathima","family":"Shihana","sequence":"first","affiliation":[{"name":"Centenary Institute of Cancer Medicine & Cell Biology The University of Sydney Camperdown New South Wales Australia"},{"name":"Edith Collins Centre (Translational Research in Alcohol Drugs and Toxicology), Sydney Local Health District Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep Manuneedhi","family":"Cholan","sequence":"additional","affiliation":[{"name":"Centenary Institute of Cancer Medicine & Cell Biology The University of Sydney Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Fraser","sequence":"additional","affiliation":[{"name":"Centenary Institute of Cancer Medicine & Cell Biology The University of Sydney Camperdown New South Wales Australia"},{"name":"School of Biomedical Engineering, Faculty of Engineering University of Sydney Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan\u00a0H.","family":"Oehlers","sequence":"additional","affiliation":[{"name":"Centenary Institute of Cancer Medicine & Cell Biology The University of Sydney Camperdown New South Wales Australia"},{"name":"Sydney School of Medicine, Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5614-1599","authenticated-orcid":false,"given":"Devanshi","family":"Seth","sequence":"additional","affiliation":[{"name":"Centenary Institute of Cancer Medicine & Cell Biology The University of Sydney Camperdown New South Wales Australia"},{"name":"Edith Collins Centre (Translational Research in Alcohol Drugs and Toxicology), Sydney Local Health District Sydney New South Wales Australia"},{"name":"Sydney School of Medicine, Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"issue":"2","key":"e_1_2_11_2_1","first-page":"147","article-title":"Alcoholic liver disease: pathogenesis and current management","volume":"38","author":"Osna NA","year":"2017","journal-title":"Alcohol Res"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60383-9"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.32"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27839"},{"issue":"3","key":"e_1_2_11_6_1","first-page":"435","article-title":"Lipid droplets and the management of cellular stress","volume":"92","author":"Jarc E","year":"2019","journal-title":"Yale J Biol 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