The incidence of both nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) have been increasing at an alarming rate. 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‐chain 3‐hydoxy acyl‐CoA 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 months old) and HCC at older age (>13 months old) without any evidence of fibrosis or cirrhosis. None of the wild‐type (WT) mice developed steatosis and HCC (n = 39), whereas HT‐LCHAD mice (n = 41) showed steatosis and ~20% (8/41) developed liver masses with histological features of HCC. Proteomic analysis of liver tissues from WT‐mice and HT‐mice 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 (p < 0.01) between WT and HT‐LCHAD 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‐LCHAD 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.

中文翻译：

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长链3-羟基酰基辅酶A脱氢酶中的缺陷导致肝细胞癌：肝细胞癌的一种新病因。

非酒精性脂肪肝疾病（NAFLD）和肝细胞癌（HCC）的发病率均以惊人的速度增加。没有肝硬化的NAFLD作为HCC的风险知之甚少。在这里，我们首次报道了长链3-羟基酰基辅酶A脱氢酶（LCHAD）缺陷的小鼠模型的生成。LCHAD外显子15缺失对纯合子小鼠具有胚胎致死性，而杂合子（HT）从年轻（3个月大）开始发展为明显的肝脂肪变性，从较大年龄（> 13个月大）开始肝癌，没有任何纤维化或肝硬化迹象。野生型（WT）小鼠均未出现脂肪变性和HCC（n = 39），而HT-LCHAD小鼠（n= 41）表现出脂肪变性，约20％（8/41）的肝脏肿块具有HCC的组织学特征。进行了无肝癌迹象的野生型小鼠和肝性小鼠肝组织的蛋白质组学分析。通过质谱鉴定丰度有显着变化的蛋白质。24种蛋白质的丰度差异显着（p<0.01）在WT和HT-LCHAD小鼠之间。发现丰度变化的蛋白质与不同的细胞反应过程相关，从碳水化合物，蛋白质和脂质的中间代谢到氧化应激，信号转导和肿瘤发生过程。HT-LCHAD小鼠肝脏的蛋白表达模式表明其易患肝癌，并提示肝线粒体脂肪酸氧化受损在肝癌的发生和发展中起重要作用。为了评估这些研究对人类疾病的影响，我们证明了HCC患者中HADHA转录物的显着下调。