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Little is known about NAFLD without cirrhosis as a risk for HCC. Here we report, for the first time, generation of a mouse model with a defect in long\u2010chain 3\u2010hydoxy acyl\u2010CoA dehydrogenase (LCHAD). The LCHAD exon 15 deletion was embryonic lethal to the homozygous mice whereas heterozygous mice (HT) develop significant hepatic steatosis starting at young age (3\u2009months old) and HCC at older age (&gt;13\u2009months old) without any evidence of fibrosis or cirrhosis. None of the wild\u2010type (WT) mice developed steatosis and HCC (<jats:italic>n<\/jats:italic> =\u200939), whereas HT\u2010LCHAD mice (<jats:italic>n<\/jats:italic> =\u200941) showed steatosis and ~20% (8\/41) developed liver masses with histological features of HCC. Proteomic analysis of liver tissues from WT\u2010mice and HT\u2010mice with no signs of HCC was conducted. Proteins with significant changes in abundance were identified by mass spectrometry. Abundance of 24 proteins was significantly different (<jats:italic>p<\/jats:italic> &lt;\u20090.01) between WT and HT\u2010LCHAD mice. The proteins found to vary in abundance are associated with different cellular response processes ranging from intermediary metabolism of carbohydrate, protein and lipid to oxidative stress, signal transduction and the process of tumorigenesis. Protein expression pattern of the HT\u2010LCHAD mouse liver indicates predisposition to HCC and suggests that impaired hepatic mitochondrial fatty acid oxidation plays an important role in the development and progression of HCC. To assess the implication of these studies in human disease, we demonstrated significant downregulation of HADHA transcripts in HCC patients.<\/jats:p>","DOI":"10.1002\/ijc.32943","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T02:53:17Z","timestamp":1583117597000},"page":"1461-1473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Defects in long\u2010chain 3\u2010hydroxy acyl\u2010CoA dehydrogenase lead to hepatocellular carcinoma: A novel etiology of hepatocellular carcinoma"],"prefix":"10.1002","volume":"147","author":[{"given":"Tripti","family":"Khare","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharad","family":"Khare","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"},{"name":"Harry S Truman Veterans' Hospital  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerry J.","family":"Angdisen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexei","family":"Stuckel","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian P.","family":"Mooney","sequence":"additional","affiliation":[{"name":"Gehrke Proteomics center University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne E.","family":"Ridenhour","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raad S.","family":"Gitan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghassan M.","family":"Hammoud","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5646-9014","authenticated-orcid":false,"given":"Jamal A.","family":"Ibdah","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Missouri  Columbia MO USA"},{"name":"Harry S Truman Veterans' Hospital  Columbia MO USA"},{"name":"Department of Medical Pharmacology and Physiology University of Missouri  Columbia MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,3,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.12.001"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.55.2.74"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.176271"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/1615-9861(200110)1:10<1249::AID-PROT1249>3.0.CO;2-1"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25797"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2011.01.023"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.10.027"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-090514-013832"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2001-12926"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(99)70506-8"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI12590"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.02.001"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26285"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)48391-3"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1172\/JCI118863","article-title":"Common missense mutation G1528C in long\u2010chain 3\u2010hydroxyacyl\u2010CoA dehydrogenase deficiency. 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