Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice.
Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice.
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DOI：
10.1007/s00204-018-2335-4
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发表时间：
2019-01
影响因子：
6.1
通讯作者：
Aoyama T
中科院分区：
文献类型：
--
作者：
Lu Y;Harada M;Kamijo Y;Nakajima T;Tanaka N;Sugiyama E;Kyogashima M;Gonzalez FJ;Aoyama T
过氧化物酶体增殖物激活受体α（Peroxisome proliferator-activated receptor α，PPARα）参与脂肪酸和胆固醇代谢的调节。高胆固醇（HC）饮食会增加发生心血管疾病（CVD）的风险;然而，尚不清楚胆固醇的毒性作用是否涉及血栓形成因子表达的变化，以及PPARα是否是此类作用所必需的。为了研究这种可能性，我们向野生型（WT）和Ppara缺失小鼠饲喂HC饲料，并测量胆固醇和甘油三酯含量、肝脏组织学、凝血因子的血清/血浆水平、凝血因子的肝脏表达、肝脏/血清硫苷脂水平、肝脏硫苷脂代谢、脂质转运蛋白的肝脏表达以及肝脏氧化应激及其相关酶。在PPara基因敲除小鼠中，HC饮食导致甘油三酯蓄积并加剧肝脏中的炎症和氧化应激，血液和肝脏中凝血因子（包括组织因子、纤溶酶原激活物抑制剂-1和羧肽酶B2）水平升高，血清和肝脏中抗血栓形成硫苷脂水平降低。这些变化在WT小鼠中不太明显。这些发现意味着胆固醇超负荷至少部分通过促进血栓形成发挥其毒性作用，继发于肝脏脂质代谢异常、炎症和氧化应激。此外，我们首次发现，除了其已知的控制脂质稳态和抑制炎症和氧化应激的作用外，PPARα还可以通过转录调节凝血因子和硫苷脂来减轻这些毒性作用。针对激活PPARα的治疗可能通过调节各种促血栓形成和抗血栓形成因子来预防HC饮食诱导的CVD。
Peroxisome proliferator-activated receptor α (PPARα) is involved in the regulation of fatty acid and cholesterol metabolism. A high-cholesterol (HC) diet increases the risk of developing cardiovascular diseases (CVD); however, it is unclear whether the toxic effects of cholesterol involve changes in thrombotic factor expression, and whether PPARα is necessary for such effects. To investigate this possibility, we fed a HC diet to wild-type (WT) and Ppara-null mice and measured cholesterol and triglyceride contents, liver histology, serum/plasma levels of coagulation factors, hepatic expression of the coagulation factors, liver/serum sulfatide levels, hepatic sulfatide metabolism, hepatic expression of lipid transporters, and hepatic oxidative stress and its relating enzymes. In Ppara-null mice, the HC diet caused triglyceride accumulation and exacerbated inflammation and oxidative stress in liver, increased levels of coagulation factors, including tissue factor, plasminogen activator inhibitor-1 and carboxypeptidase B2 in blood and liver, and decreased levels of anti-thrombotic sulfatides in serum and liver. These changes were much less marked in WT mice. These findings imply that cholesterol overload exerts its toxic effects at least in part by enhancing thrombosis, secondary to abnormal hepatic lipid metabolism, inflammation, and oxidative stress. Moreover, we reveal for the first time that PPARα can attenuate these toxic effects by transcriptional regulation of coagulation factors and sulfatides, in addition to its known effects of controlling lipid homeostasis and suppressing inflammation and oxidative stress. Therapies aimed at activating PPARα might prevent HC diet-induced CVD through modulating various pro- and anti-thrombotic factors.
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DOI：
10.1016/j.bbadis.2014.12.011
发表时间：
2015-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Komatsu M;Kimura T;Yazaki M;Tanaka N;Yang Y;Nakajima T;Horiuchi A;Fang ZZ;Joshita S;Matsumoto A;Umemura T;Tanaka E;Gonzalez FJ;Ikeda S;Aoyama T
通讯作者：
Aoyama T
影响因子：
64.8
作者：
Kersten, S;Desvergne, B;Wahli, W
通讯作者：
Wahli, W
影响因子：
13.2
作者：
Ansquer, JC;Foucher, C;Steiner, G
通讯作者：
Steiner, G
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria
影响因子：
29
作者：
Chakravarthy, MV;Pan, ZJ;Semenkovich, CF
通讯作者：
Semenkovich, CF