Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect.
Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect.
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过氧化物酶体增殖物激活受体 α 激活可诱导肝脂肪变性，表明有不良作用
DOI：
10.1371/journal.pone.0099245
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Yan F;Wang Q;Xu C;Cao M;Zhou X;Wang T;Yu C;Jing F;Chen W;Gao L;Zhao J
非酒精性脂肪性肝病（NAFLD）的特征是肝脏甘油三酯蓄积，范围从脂肪变性到脂肪性肝炎和肝硬化。NAFLD是心血管疾病的危险因素，与代谢综合征有关。抗高血压药物被推荐作为NAFLD患者治疗的一部分。虽然贝特类药物激活过氧化物酶体增殖物激活受体α（PPARα），导致血清甘油三酯水平降低，但这些药物对NAFLD的影响仍存在争议。临床研究报告称，PPARα激活不会改善肝脂肪变性。本研究旨在探讨过氧化物酶体增殖物激活受体α（PPARα）激活对肝脏甘油三酯蓄积和肝脏脂肪变性的影响及其机制。雄性C57 BL/6 J小鼠、Pparα-null小鼠和HepG 2细胞用最常用的贝特类药物之一非诺贝特处理。给予低剂量和高剂量的非诺贝特。油红O染色及电镜观察肝脏脂肪变性。值得注意的是，在非诺贝特处理的小鼠中，血清甘油三酯水平降低，肝脏甘油三酯含量以剂量依赖性方式增加。肝脏切片油红O染色显示，非诺贝特喂养的小鼠积累了丰富的中性脂质。非诺贝特还增加HepG 2细胞内甘油三酯含量。固醇调节元件结合蛋白1c（SREBP-1c）和与脂肪生成相关的关键基因的表达在非诺贝特处理的小鼠肝脏和HepG 2细胞中以剂量依赖性方式增加。然而，在用非诺贝特处理的Pparα-null小鼠中，该作用强烈受损。非诺贝特处理通过PPARα与SREBP-1c基因的DR 1基序直接结合诱导成熟SREBP-1c表达。总而言之，这些研究结果表明了PPARα激活增加肝脏甘油三酯积聚的分子机制，并表明贝特类药物对肝脏脂肪变性的发病机制有不良影响。
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an adverse effect of fibrates on the pathogenesis of hepatic steatosis.
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影响因子：
11.5
作者：
Adkins, JC;Faulds, D
通讯作者：
Faulds, D
DOI：
10.1016/j.bbalip.2004.04.004
发表时间：
2004-07-05
影响因子：
4.8
作者：
Le Jossic-Corcos, C;Duclos, S;Bournot, P
通讯作者：
Bournot, P
影响因子：
8.2
作者：
Bajaj, M.;Suraamornkul, S.;DeFronzo, R. A.
通讯作者：
DeFronzo, R. A.
非酒精性脂肪肝病的发病机理。
DOI：
10.1093/qjmed/hcp158
发表时间：
2010-02
期刊：
QJM : monthly journal of the Association of Physicians
影响因子：
--
作者：
Dowman JK;Tomlinson JW;Newsome PN
通讯作者：
Newsome PN
影响因子：
14.8
作者：
Chen, Qijie;Kon, Junko;Mitaka, Toshihiro
通讯作者：
Mitaka, Toshihiro