Beyond reasonable doubt: who is the culprit in lipotoxicity in NAFLD/NASH?
Beyond reasonable doubt: who is the culprit in lipotoxicity in NAFLD/NASH?
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DOI：
10.1002/hep.25721
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发表时间：
2012-06
期刊：
影响因子：
13.5
通讯作者：
Arteel, Gavin E
中科院分区：
文献类型：
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作者：
Arteel, Gavin E
2型糖尿病和非酒精性脂肪性肝炎（NASH）与胰岛素抵抗和胆固醇稳态紊乱有关。我们研究了肝脏胆固醇蓄积伴胰岛素抵抗的基础及其与NASH发病机制的相关性。Alms 1突变体（foz/foz）和野生型NOD.B10小鼠喂食含有不同百分比胆固醇的高脂肪饮食;测定肝脏脂质池和胆固醇周转途径。肝细胞暴露于糖尿病foz/foz小鼠体内循环的胰岛素浓度。肝脏胆固醇积聚归因于通过激活固醇调节元件结合蛋白2（SREBP-2）上调低密度脂蛋白受体、减少胆汁酸的生物转化以及抑制胆汁中胆固醇和胆汁酸排泄的小管途径。将原代肝细胞暴露于糖尿病Alms 1小鼠中循环的胰岛素浓度，复制了SREBP-2和低密度脂蛋白受体的增加以及胆盐输出泵的抑制。从饮食中去除胆固醇可防止游离胆固醇和NASH的肝脏蓄积;增加饮食胆固醇水平可加剧游离胆固醇的肝脏蓄积、肝细胞损伤或凋亡、巨噬细胞募集和肝纤维化。在肥胖的糖尿病小鼠中，高胰岛素血症改变了胆固醇稳态的核转录调节因子，导致游离胆固醇的肝脏蓄积;产生的细胞毒性介导脂肪变性向NASH的转变。
Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH.