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(Pten缺陷)小鼠的肝脏中，中央静脉周围的肝细胞含有脂滴。到40周时，Pten缺陷的肝脏表现为肝细胞肿胀、Mallory小体、小叶炎性细胞浸润、轻度的肝窦纤维性改变、腺瘤以及整个肝小叶加重的脂肪改变。78周龄时，Pten基因缺陷小鼠的肝脏会发生肝细胞癌。这些肝脏病变的组织学结果和自然病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，导致著名的核转录因子PPARγ和SREBP1c表达增加。这些核因子的激活增强了其下游分子如aP2、adips…的表达。更多的是，脂联素、SCD1、脂肪酸合成酶和酰辅酶A羧化酶进而促进肝细胞中甘油三酯的合成，从而导致脂肪肝。我们认为，在脂滴过多的肝细胞中，β氧化促进酶如酰辅酶A氧化酶、L-PBE和PTL的表达增加，产生氧化应激，损害自身，从而导致肝炎。Pten缺陷肝脏对肠道细菌来源的内毒素的超敏反应也是肝炎发生和加重的原因之一。Pten缺陷肝细胞过度氧化应激所致的DNA氧化损伤，以及以Akt和MAPK活化为基础的Pten缺陷肝细胞增殖增强，参与了肿瘤的发生发展。Pten缺陷肝组织中油酸的增加和硬脂酸的减少也与肿瘤的形成有关。此外，我们还利用来自Pten缺陷的肝细胞和野生型肝细胞的RNA进行了基因芯片，以寻找与Pten缺陷的肝脏炎症、纤维化和癌变进展相关的候选基因。结果提示，骨桥蛋白是一种激活Th1细胞的细胞因子，在Pten缺陷小鼠肝脏病变的发生发展过程中起重要作用。对人NASH来源的肝细胞癌和非癌病变的免疫组织学分析表明，PTEN的表达减少和氧化应激的积累与人类NASH致癌的发生有关。这些发现表明，在一些人类NASH中，肝脏损害的发生机制与上文所述的Pten缺陷肝脏相同。较少

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