PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase.
PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase.
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DOI：
10.1016/j.celrep.2015.02.022
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发表时间：
2015-03-10
期刊：
影响因子：
8.8
通讯作者：
Bodmer R
中科院分区：
文献类型：
--
作者：
Diop SB;Bisharat-Kernizan J;Birse RT;Oldham S;Ocorr K;Bodmer R
肥胖和代谢综合征与脂毒性心肌病的风险增加有关，脂毒性心肌病与心脏中脂质的过度积聚密切相关。肥胖和2型糖尿病相关疾病与转录辅因子PGC-1α的表达改变有关，PGC-1α调节参与能量代谢的基因的表达。使用果蝇，我们确定PGC-1/spargel（PGC-1/srl）是高脂饮食（HFD）诱导的脂毒性心肌病的关键拮抗剂。我们发现，HFD诱导的脂质积聚和心功能障碍被PGC-1/srl功能降低所模拟，并被PGC-1/srl过表达所逆转。此外，HFD喂养通过提高TOR信号传导和抑制果蝇脂肪细胞甘油三酯脂肪酶（ATGL，Brummer）的表达来降低PGC-1/srl表达，这两者都作为PGC-1/srl的上游调节剂起作用。脂肪生成转录因子SREBP也有助于HFD诱导的心脏脂毒性，可能与PGC-1/srl平行。这些结果表明，调节脂毒性心脏功能障碍的关键代谢基因的调控网络。
Obesity and metabolic syndrome are associated with an increased risk for lipotoxic cardiomyopathy, which is strongly correlated with excessive accumulation of lipids in the heart. Obesity- and type 2 diabetes-related disorders have been linked to altered expression of the transcriptional cofactor PGC-1α, which regulates the expression of genes involved in energy metabolism. Using Drosophila, we identify PGC-1/spargel (PGC-1/srl) as a key antagonist of high-fat diet (HFD)-induced lipotoxic cardiomyopathy. We find that HFD-induced lipid accumulation and cardiac dysfunction are mimicked by reduced PGC-1/srl function and reversed by PGC-1/srl overexpression. Moreover, HFD feeding lowers PGC-1/srl expression by elevating TOR signaling and inhibiting expression of the Drosophila adipocyte triglyceride lipase (ATGL, Brummer), both of which function as upstream modulators of PGC-1/srl. The lipogenic transcription factor SREBP also contributes to HFD-induced cardiac lipotoxicity, likely in parallel with PGC-1/srl. These results suggest a regulatory network of key metabolic genes that modulates lipotoxic heart dysfunction.