Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD.
Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD.
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DOI：
10.1136/gutjnl-2015-310798
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发表时间：
2016-07
期刊：
影响因子：
24.5
通讯作者：
Guillou H
中科院分区：
文献类型：
--
作者：
Montagner A;Polizzi A;Fouché E;Ducheix S;Lippi Y;Lasserre F;Barquissau V;Régnier M;Lukowicz C;Benhamed F;Iroz A;Bertrand-Michel J;Al Saati T;Cano P;Mselli-Lakhal L;Mithieux G;Rajas F;Lagarrigue S;Pineau T;Loiseau N;Postic C;Langin D;Wahli W;Guillou H
过氧化物酶体增殖物激活受体α（Peroxisome proliferator-activated receptor α，PPARα）是一种在组织中表达的核受体，具有高氧化活性，在代谢中起核心作用。在这项工作中，我们研究了肝细胞PPARα在非酒精性脂肪性肝病（NAFLD）中的作用。我们构建了一种新的肝细胞特异性PPARα基因敲除（Pparαhep−/−）小鼠模型。使用这种新的模型，我们进行了非诺贝特治疗后的转录组学分析。接下来，我们研究了哪些生理挑战会影响PPARα。此外，我们测量了禁食期间肝细胞PPARα活性对全身代谢和成纤维细胞生长因子21产生的贡献。最后，我们确定了肝细胞特异性PPARα缺乏在不同脂肪变性模型和衰老过程中的影响。肝细胞PPARα缺失损害脂肪酸代谢，导致禁食期间和两种脂肪变性临床前模型中的肝脏脂质蓄积。禁食小鼠在夜间表现出急性的PPARα依赖性肝细胞活性，相应地增加了循环游离脂肪酸，这可以通过脂肪细胞脂解进一步刺激。与Pparα−/−小鼠相比，禁食导致Pparαhep−/−小鼠出现轻度低血糖和体温过低，这表明非肝组织中的PPARα活性发挥作用。与这一观察结果一致，Pparα−/−小鼠在衰老过程中变得超重，而Pparαhep−/−保持苗条。然而，与Pparα−/−小鼠一样，喂食标准饮食的Pparαhep−/−小鼠在衰老过程中发生了肝脏脂肪变性。总之，这些发现强调了肝细胞PPARα作为NAFLD药物靶点的潜力。
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD). We constructed a novel hepatocyte-specific PPARα knockout (Pparαhep−/−) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing. Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparαhep−/− mice when compared with Pparα−/− mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα−/− mice became overweight during ageing while Pparαhep−/− remained lean. However, like Pparα−/− mice, Pparαhep−/− fed a standard diet developed hepatic steatosis in ageing. Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.