CIDEC/FSP27 is regulated by peroxisome proliferator-activated receptor alpha and plays a critical role in fasting- and diet-induced hepatosteatosis.
CIDEC/FSP27 is regulated by peroxisome proliferator-activated receptor alpha and plays a critical role in fasting- and diet-induced hepatosteatosis.
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DOI：
10.1002/hep.27607
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发表时间：
2015-04
期刊：
影响因子：
13.5
通讯作者：
Baldan, Angel
中科院分区：
文献类型：
--
作者：
Langhi, Cedric;Baldan, Angel
诱导细胞死亡的dfa样效应物c （CIDEC，在啮齿类动物中也称为FSP27或脂肪特异性蛋白27）是一种脂滴相关蛋白，可促进细胞内甘油三酯储存。CIDEC/Fsp27在脂肪组织中高表达，但在正常肝脏中检测不到。然而，在小鼠和患者中，它的肝脏表达在禁食或遗传或饮食诱导的肝骨化症中升高。本研究表明，在小鼠和人肝细胞中，CIDEC/Fsp27是核受体PPARα（过氧化物酶体增殖物激活受体α）的直接转录靶点，阻止Fsp27的诱导会加速PPARα刺激的脂肪酸氧化。我们发现，腺病毒介导的肝Fsp27沉默可以在不改变血浆脂质的情况下消除空腹诱导的肝脂肪变性。最后，我们报道了抗fsp27 shRNA和PPARα激动剂协同改善高脂饮食小鼠的肝纤维化。总之，我们的数据强调了CIDEC/Fsp27在生理性和病理性肝脂肪变性下甘油三酯稳态中的生理重要性。我们的研究结果还表明，服用贝特类药物的患者可能有肝脏CIDEC水平升高，这可能限制肝脏甘油三酯的有效动员和分解代谢。
The cell death-inducing DFFA-like effector c (CIDEC; also known in rodents as FSP27 or fat-specific protein 27) is a lipid droplet-associated protein that promotes intracellular triglyceride storage. CIDEC/Fsp27 is highly expressed in adipose tissue but undetectable in normal liver. Its hepatic expression, however, rises during fasting or under genetic or diet-induced hepatosteatosis in both mice and patients. Herein, we demonstrate that CIDEC/Fsp27 is a direct transcriptional target of the nuclear receptor PPARα (peroxisome proliferator activated receptor alpha) in both mouse and human hepatocytes, and that preventing Fsp27 induction accelerates PPARα-stimulated fatty acid oxidation. We show that adenoviral-mediated silencing of hepatic Fsp27 abolishes fasting-induced liver steatosis in the absence of changes in plasma lipids. Finally, we report that anti-Fsp27 shRNA and PPARα agonists synergize to ameliorate hepatosteatosis in mice fed a high fat diet. Together, our data highlight the physiological importance of CIDEC/Fsp27 in triglyceride homeostasis under both physiological and pathological liver steatosis. Our results also suggest that patients taking fibrates likely have elevated levels of hepatic CIDEC, which may limit the efficient mobilization and catabolism of hepatic triglycerides.
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