{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:26:21Z","timestamp":1790295981972,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2010,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>The actual risk factors that drive hepatic inflammation during the transition from steatosis to steatohepatitis are unknown. We recently demonstrated that hyperlipidemia-prone apolipoprotein E\u2013deficient (ApoE\u2212\/\u2212) mice exhibit hepatic steatosis and increased susceptibility to hepatic inflammation and advanced fibrosis. Because the proinflammatory 5-lipoxygenase (5-LO) pathway was found to be up-regulated in these mice and given that 5-LO deficiency confers cardiovascular protection to ApoE\u2212\/\u2212 mice, we determined the extent to which the absence of 5-LO would alter liver injury in these mice. Compared with ApoE\u2212\/\u2212 mice, which showed expected hepatic steatosis and inflammation, ApoE\/5-LO double-deficient (ApoE\u2212\/\u2212\/5-LO\u2212\/\u2212) mice exhibited reduced hepatic inflammation, macrophage infiltration, tumor necrosis factor \u03b1 (TNF-\u03b1), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, caspase-3 and nuclear factor-\u03baB (NF-\u03baB) activities, and serum alanine aminotransferase levels in the absence of changes in hepatic steatosis. The lack of 5-LO produced a remarkable insulin-sensitizing effect in the adipose tissue because peroxisome proliferator-activated receptor \u03b3, insulin receptor substrate-1, and adiponectin were up-regulated, whereas c-Jun amino-terminal kinase phosphorylation and MCP-1 and IL-6 expression were down-regulated. On the other hand, hepatocytes isolated from ApoE\u2212\/\u2212\/5-LO\u2212\/\u2212 mice were more resistant to TNF-\u03b1\u2013induced apoptosis. The 5-LO products leukotriene (LT) B4, LTD4, and 5-HETE consistently triggered TNF-\u03b1\u2013induced apoptosis and compromised hepatocyte survival by suppressing NF-\u03baB activity in the presence of actinomycin D. Moreover, ApoE\u2212\/\u2212\/5-LO\u2212\/\u2212 mice were protected against sustained high-fat diet (HFD)-induced liver injury and hepatic inflammation, macrophage infiltration and insulin resistance were significantly milder than those of ApoE\u2212\/\u2212 mice. Finally, pharmacological inhibition of 5-LO significantly reduced hepatic inflammatory infiltrate in the HFD and<\/jats:bold>\n                      <jats:bold>ob\/ob<\/jats:bold>\n                      <jats:bold>models of fatty liver disease.<\/jats:bold>\n                      <jats:bold>Conclusion:<\/jats:bold>\n                      <jats:bold>These combined data indicate that hyperlipidemic mice lacking 5-LO are protected against hepatic inflammatory injury, suggesting that 5-LO is involved in mounting hepatic inflammation in metabolic disease. (Hepatology 2010.)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23463","type":"journal-article","created":{"date-parts":[[2009,11,30]],"date-time":"2009-11-30T15:03:02Z","timestamp":1259593382000},"page":"817-827","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":99,"title":["5-Lipoxygenase Deficiency Reduces Hepatic Inflammation and Tumor Necrosis Factor \u03b1\u2013Induced Hepatocyte Damage in Hyperlipidemia-Prone Apoe-Null Mice"],"prefix":"10.1097","volume":"51","author":[{"given":"Marcos","family":"Mart\u00ednez-Clemente","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e0lia","family":"Ferr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Gonz\u00e1lez-P\u00e9riz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"L\u00f3pez-Parra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Horrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Titos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Mor\u00e1n-Salvador","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Miquel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Arroyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin D.","family":"Funk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Cl\u00e0ria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-13-20241201","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1056\/NEJMra011775","article-title":"Nonalcoholic fatty liver disease.","volume":"346","author":"Angulo","year":"2002","journal-title":"N Engl J Med"},{"key":"R2-13-20241201","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/ncpgasthep0084","article-title":"Mechanisms of disease: pathogenesis of nonalcoholic fatty liver disease.","volume":"2","author":"Sanyal","year":"2005","journal-title":"Nat Clin Pract Gastroenterol Hepatol"},{"key":"R3-13-20241201","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1002\/hep.22845","article-title":"; The RISC Investigators. 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