The involvement of lipid signaling to the onset and progression of nonalcoholic steatohepatitis and the development of hepatocellular carcinoma

在10周龄肝细胞特异性Pten缺陷小鼠的肝脏中，中心静脉周围的肝细胞含有脂滴。到40周时，Pten缺乏肝表现为肝细胞球囊化，Mallory小体，小叶炎性细胞浸润，轻度窦状纤维化改变，肝小叶腺瘤和脂肪改变的严重程度增加。肝细胞癌在Pten缺陷小鼠的肝脏中发展到78周龄。这些肝脏病变的组织学表现和自然过程与人类非酒精性脂肪性肝炎（NASH）的报道惊人地相似。因此，Pten缺陷小鼠被认为是人类NASH的动物模型。PTEN缺乏诱导肝细胞中PI3激酶的激活，导致PPARγ和SREBP1c这两种著名的核转录因子的表达增加。这些核因子的激活增强了其下游分子如aP2、adips、More in、脂联素、SCD1、脂肪酸合成酶、酰基辅酶a羧化酶的表达，进而促进肝细胞内甘油三酯的合成，导致脂肪肝。我们认为，在拥有过多脂滴的肝细胞中，β-氧化促进酶（如酰基辅酶a氧化酶、L-PBE和PTL）的表达增加会产生氧化应激，从而损伤自身，导致肝炎。Pten缺乏的肝脏对来自肠道细菌的LPS的超敏反应也有助于肝炎的发生和恶化。在Pten缺陷肝脏中，过度氧化应激诱导的氧化DNA损伤和基于Akt和MAPK激活的Pten缺陷肝细胞增殖增加有助于肿瘤的发展。Pten缺乏肝脏中油酸升高、硬脂酸降低也与肿瘤的形成有关。此外，我们使用来自Pten缺陷肝细胞和野生型肝细胞的RNA进行cDNA微阵列研究，以寻找Pten缺陷肝中与炎症、纤维化和癌变进展相关的候选基因。因此，我们认为骨桥蛋白（一种激活Th1细胞的细胞因子）在Pten缺陷小鼠肝脏病变的发展中发挥了重要作用。对人类NASH引起的肝细胞癌和非癌性病变的免疫组织学分析表明，PTEN表达的降低和氧化应激的积累与人类NASH致癌性的发展有关。这些发现表明，一些人类NASH的肝脏病变与上述Pten缺陷肝脏的机制相同。少

In the livers of 10-week-old hepatocyte-specific Pten deficient (Pten deficient) mice, hepatocytes around the central vein contains lipid droplets. By 40 weeks, Pten deficient livers show ballooning hepatocytes, Mallory bodies, lobular inflammatory cells infiltration, mild sinusoidal fibrogenic changes, and adenoma as well as fatty changes of increased severity throughout the hepatic lobules. Hepatocellular carcinomas develop in Pten deficient mice livers by 78 weeks of age. These histological findings and natural course of hepatic lesions are strikingly similar to those reported for nonalcoholic steatohepatitis (NASH) in humans. Thus, Pten deficient mice are thought to be an animal model of human NASH.PTEN deficiency induces the activation of PI3 kinase in hepatocytes, resulting in the increased expression of PPARγ and SREBP1c that are famous nuclear transcriptional factors. The activation of these nuclear factors enhance the expression of their downstream molecules such as aP2, adips … More in, adiponectin, SCD1, fatty acid synthetase, and acyl-CoA carboxylase and then promote the synthesis of triglyceride in hepatocytes, resulting in the fatty livers. We consider that the increased expression of β-oxidation-promoting enzymes such as acyl-CoA oxidase, L-PBE, and PTL in hepatocytes possessing excessive lipid droplets produces oxidative stress that injuries themselves, resulting in hepatitis. The hypersensitivity of Pten deficient livers to LPS derived from intestinal bacteria also contributes to the onset and exacerbation of hepatitis. Oxidative DNA damage induced by excessive oxidative stress in the Pten deficient livers and increased proliferation of Pten deficient hepatocytes based on the activation of Akt and MAPK contribute to the tumor development. The increase of oleic acid and the decrease of stearic acid in the Pten deficient livers are also related to the tumor formation. Moreover, we carried out cDNA microarray using RNA derived from Pten deficient and wild type hepatocytes to find the candidate genes related to the progression of inflammation, fibrosis, and carcinogenesis in the Pten deficient livers. As a result, it was suggested that osteopontin, a cytokine that activates Th1 cells, played an important role in the development of the hepatic lesions of Pten deficient mice.The immunohiostological analysis of hepatocellular carcinoma and non-cancerous lesion derived from human NASH suggested that decreased expression of PTEN and accumulation of oxidative stress were related to the development of NASH containing carcinogenesis in humans. These findings suggest that hepatic lesions in some of human NASH develop based on the same mechanisms as those seen in Pten deficient livers as described above. Less