Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis
Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis
复制标题
DOI：
10.1152/ajpendo.90764.2008
复制
发表时间：
2009-08-01
影响因子：
5.1
通讯作者：
Adeli, Khosrow
中科院分区：
文献类型：
--
作者：
Basciano, Heather;Miller, Abigale E.;Adeli, Khosrow
Basciano H, Miller AE, Naples M, Baker C, Kohen R, Xu E, Su Q, Allister EM, Wheeler MB, Adeli K.膳食胆固醇对胰岛素抵抗和肝脏脂肪变性动物代谢的影响。[J] .中国生物医学工程学报，2009,31(2):559 - 563。首次发表于2009年6月9日；doi: 10.1152 / ajpendo.90764.2008。虽然膳食胆固醇在动脉粥样硬化中的作用已被证实，但其致糖尿病的潜力和相关的代谢紊乱尚未被报道。采用饮食诱导的胰岛素抵抗和血脂异常仓鼠模型来研究膳食胆固醇的致脂和致糖尿病作用。对仓鼠进行了代谢研究，仓鼠的饮食中含有丰富的果糖（40%）、脂肪（30%）和胆固醇（0.05-0.25%）（FFC）和其他试验饮食。短期饲喂FFC日粮可引起胰岛素抵抗、葡萄糖耐受不良、高甘油三酯血症和高胆固醇血症。长时间饲喂FFC日粮（6-22周）导致严重的肝脏脂肪变性、葡萄糖耐受不良和空腹血糖轻度升高，提示向2型糖尿病发展，但未诱导β细胞功能障碍。饮食引起的代谢变化，包括血脂异常和胰岛素抵抗，是胆固醇浓度依赖的，只有在高果糖和高脂肪的饮食背景下才会显著诱导。饲喂FFC可显著提高肝脏和血浆甘油三酯水平，这可能是由于肝脏硬脂酰辅酶a去饱和酶水平是饲料水平的10 ~ 15倍（P < 0.03）。肝脏胰岛素抵抗明显基于胰岛素受体β、IRS-1和IRS-2酪氨酸磷酸化的减少以及蛋白酪氨酸磷酸酶1B蛋白质量的增加。有趣的是，核肝X受体（LXR）靶基因如ABCA1在FFC日粮中上调，并且在日粮中添加LXR激动剂（而不是膳食胆固醇）会加重血脂异常、葡萄糖耐受不良，靶mRNA和蛋白的上调与膳食胆固醇相似。总之，这些数据清楚地表明，膳食胆固醇与膳食脂肪和果糖协同作用，是仓鼠模型中代谢紊乱严重程度的主要决定因素。膳食胆固醇似乎诱导肝脏胆固醇酯和甘油三酯积累，饮食诱导的LXR激活（通过胆固醇衍生的氧化固醇）可能是一个关键的潜在机制。
Basciano H, Miller AE, Naples M, Baker C, Kohen R, Xu E, Su Q, Allister EM, Wheeler MB, Adeli K. Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis. Am J Physiol Endocrinol Metab 297: E462-E473, 2009. First published June 9, 2009; doi: 10.1152/ajpendo.90764.2008. Although the atherogenic role of dietary cholesterol has been well established, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05-0.25%) (FFC) and other test diets. Short-term feeding of the FFC diet induced insulin resistance, glucose intolerance, hypertriglyceridemia, and hypercholesterolemia. Prolonged feeding (6-22 wk) of the FFC diet led to severe hepatic steatosis, glucose intolerance, and mild increases in fasting blood glucose, suggesting progression toward type 2 diabetes, but did not induce beta-cell dysfunction. Metabolic changes induced by the diet, including dyslipidemia and insulin resistance, were cholesterol concentration dependent and were only markedly induced on a high-fructose and high-fat dietary background. There were significant increases in hepatic and plasma triglyceride with FFC feeding, likely due to a 10- to 15-fold induction of hepatic stearoyl-CoA desaturase compared with chow levels (P < 0.03). Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-beta, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, and upregulation of target mRNA and proteins similar to that of dietary cholesterol. In summary, these data clearly implicate dietary cholesterol, synergistically acting with dietary fat and fructose, as a major determinant of the severity of metabolic disturbances in the hamster model. Dietary cholesterol appears to induce hepatic cholesterol ester and triglyceride accumulation, and diet-induced LXR activation (via cholesterol-derived oxysterols) may possibly be one key underlying mechanism.