Kashireddy Papreddy V, Rao M Sambasiva
Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
Hepatol Res. 2004 Oct;30(2):104-110. doi: 10.1016/j.hepres.2004.06.004.
Pathogenesis of steatohepatitis, a common liver disease, remains controversial. It is proposed that fatty liver with a second hit capable of inducing necroinflammation results in nonalcoholic steatohepatitis. Long chain and very long chain fatty acids are considered important in induction of steatohepatitis. Peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in beta-oxidation of long chain and very long chain fatty acids and mitogenic effect caused by peroxisome proliferators in the liver. To determine the role of PPARalpha in the pathogenesis of steatohepatitis and compensatory liver cell hyperplasia, we have used PPARalpha null mice and methionine and choline deficient nutritional model. Male and female PPARalpha null mice and wild type mice were fed methionine and choline deficient diet (MCDD) or normal chow for 4 weeks. Livers were analyzed morphologically for steatosis, steatohepatitis and hepatocyte proliferation (PCNA labeling) and biochemically for triglyceride levels. In addition, serum alanine transaminase, aspartate transaminase and triglyceride levels were measured. In MCDD fed PPARalpha null mice there was severe steatohepatitis and very high liver triglyceride levels compared to wild type mice. Serum aspartate transaminase levels were also significantly higher in MCDD fed PPARalpha null mice compared to wild type mice. The severity of steatohepatitis in MCDD fed male and female PPARalpha null mice was greater compared to wild type mice fed the same diet. The PCNA labeling index was similar in PPARalpha null mice and wild type mice fed MCDD, and significantly higher in both the groups compared to the mice fed control diet. These findings indicate that defective fatty acid oxidation aggravates steatohepatitis caused by methionine and choline deficiency and further establishes the role of long chain and very long chain fatty acids in the pathogenesis of steatohepatitis. In addition, the results of this study also indicate that there is no difference between males and females in the severity of steatohepatitis induced by MCDD and lack of PPARalpha does not affect compensatory hyperplasia in the liver.
脂肪性肝炎是一种常见的肝脏疾病，其发病机制仍存在争议。有人提出，伴有能够诱导坏死性炎症的二次打击的脂肪肝会导致非酒精性脂肪性肝炎。长链和极长链脂肪酸被认为在脂肪性肝炎的诱导中起重要作用。过氧化物酶体增殖物激活受体α（PPARα）在长链和极长链脂肪酸的β氧化以及过氧化物酶体增殖物在肝脏中引起的促有丝分裂作用中发挥重要作用。为了确定PPARα在脂肪性肝炎发病机制和代偿性肝细胞增生中的作用，我们使用了PPARα基因敲除小鼠以及蛋氨酸和胆碱缺乏的营养模型。将雄性和雌性PPARα基因敲除小鼠及野生型小鼠喂食蛋氨酸和胆碱缺乏饮食（MCDD）或正常食物4周。对肝脏进行形态学分析以检测脂肪变性、脂肪性肝炎和肝细胞增殖（PCNA标记），并进行生化分析以检测甘油三酯水平。此外，还测量了血清丙氨酸转氨酶、天冬氨酸转氨酶和甘油三酯水平。与野生型小鼠相比，喂食MCDD的PPARα基因敲除小鼠出现严重的脂肪性肝炎且肝脏甘油三酯水平非常高。与野生型小鼠相比，喂食MCDD的PPARα基因敲除小鼠血清天冬氨酸转氨酶水平也显著更高。与喂食相同饮食的野生型小鼠相比，喂食MCDD的雄性和雌性PPARα基因敲除小鼠的脂肪性肝炎严重程度更高。喂食MCDD的PPARα基因敲除小鼠和野生型小鼠的PCNA标记指数相似，且与喂食对照饮食的小鼠相比，两组的PCNA标记指数均显著更高。这些发现表明，脂肪酸氧化缺陷会加重蛋氨酸和胆碱缺乏引起的脂肪性肝炎，并进一步证实了长链和极长链脂肪酸在脂肪性肝炎发病机制中的作用。此外，本研究结果还表明，MCDD诱导的脂肪性肝炎严重程度在雄性和雌性之间没有差异，且缺乏PPARα不影响肝脏的代偿性增生。
