Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice
Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice
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DOI：
10.1111/j.1440-1746.2009.05996.x
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发表时间：
2009-10-01
影响因子：
4.1
通讯作者：
Farrell, Geoffrey C.
中科院分区：
文献类型：
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作者：
Larter, Claire Z.;Yeh, Matthew M.;Farrell, Geoffrey C.
背景和目的：我们之前报道过，肥胖、高胆固醇血症、糖尿病的 foz/foz 小鼠在喂食高脂肪 (HF) 饮食 12 个月后会出现脂肪性肝炎。我们现在报道了与代谢异常相关的脂肪性肝炎的早期发作，并阐明了在这种新型非酒精性脂肪性肝炎 (NASH) 模型中，膳食脂肪和体脂分配对脂肪变性严重程度、肝损伤和炎症募集的作用。方法：Foz/foz（Alms1 突变体）和野生型（WT）小鼠喂食高频饮食或食物，并在 2、6、12 和 12 岁研究代谢特征和肝脏组织学。 24 周。结果：HF 喂养 12 周后，foz/foz 小鼠出现肥胖和糖尿病，血清脂联素下降约 70%。此时出现肝肿大，对应于脂肪扩张的平台期和脂肪炎症的增加。肝脏组织学显示轻度炎症、肝细胞膨胀以及脂肪变性。到 24 周时，高频喂养的 foz/foz 小鼠出现了严重的脂肪性肝炎（明显的脂肪变性、丙氨酸转氨酶升高、膨胀、炎症、纤维化），而饮食和基因控制仅显示出简单的脂肪变性。虽然脂肪变性与肝脏脂肪生成相关（脂肪酸合成酶活性增加表明），但脂肪性肝炎与 CD36 水平显着升高相关，这表明脂肪酸摄取活跃，可能是在过氧化物酶体增殖物激活受体-γ 的影响下。结论：在遗传上易患肥胖和糖尿病的小鼠中，高频喂养导致脂肪组织限制容纳多余能量，导致脂质分配到肝脏，并将单纯性脂肪变性转化为脂肪变性。纤维化脂肪性肝炎。高频喂养使脂肪储存“饱和”、降低血清脂联素并导致脂肪性肝炎中的肝脏炎症，这可能为代谢综合征中 NASH 的发病机制提供线索。
Background and Aims:We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model.Methods:Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks.Results:After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-gamma.Conclusion:In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding 'saturates' adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome.