A Drosophila model of high sugar diet-induced cardiomyopathy.
A Drosophila model of high sugar diet-induced cardiomyopathy.
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DOI：
10.1371/journal.pgen.1003175
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Cagan R
中科院分区：
文献类型：
--
作者：
Na J;Musselman LP;Pendse J;Baranski TJ;Bodmer R;Ocorr K;Cagan R
长期以来，高碳水化合物饮食一直与进行性心脏功能障碍有关，但慢性高糖导致心力衰竭的机制仍然知之甚少。在这里，我们结合饮食、遗传学和生理学，建立了一种成年果蝇慢性高糖诱发心脏病的模型。我们发现心功能恶化伴有纤维性胶原堆积、胰岛素信号缺陷和脂肪堆积。结果是寿命缩短，在胰岛素和P38信号减少的情况下，寿命更短。我们提供了氨基己糖流量的证据，这是一种由葡萄糖进入的代谢途径。氨基己糖流量增加会导致心脏功能缺陷和结构损伤；相反，心脏特异性途径活性的降低可以防止糖诱导的心脏功能障碍。我们的数据建立了果蝇作为一个有用的系统，用于探索饮食诱导的心脏功能障碍的特定方面，并强调将氨基己糖生物合成途径中的酶作为候选治疗靶点。心脏病仍然是美国人口中最常见的死亡来源。西方饮食被认为是一个重要因素，尽管饮食中高水平的糖分和脂肪导致心力衰竭的机制仍然存在争议。在这里，我们使用果蝇来探索饮食在进行性心力衰竭中的作用。我们发现，饮食中糖分水平的升高足以直接导致果蝇进行性心力衰竭，包括心律失常、缩短分数减少和纤维化等方面。我们证明了多种细胞途径的重要性，包括氨基己糖生物合成途径，对于调节这些进行性缺陷是重要的，这表明了一条潜在的治疗途径。
Diets high in carbohydrates have long been linked to progressive heart dysfunction, yet the mechanisms by which chronic high sugar leads to heart failure remain poorly understood. Here we combine diet, genetics, and physiology to establish an adult Drosophila melanogaster model of chronic high sugar-induced heart disease. We demonstrate deterioration of heart function accompanied by fibrosis-like collagen accumulation, insulin signaling defects, and fat accumulation. The result was a shorter life span that was more severe in the presence of reduced insulin and P38 signaling. We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Increased hexosamine flux led to heart function defects and structural damage; conversely, cardiac-specific reduction of pathway activity prevented sugar-induced heart dysfunction. Our data establish Drosophila as a useful system for exploring specific aspects of diet-induced heart dysfunction and emphasize enzymes within the hexosamine biosynthetic pathway as candidate therapeutic targets. Heart disease remains the most common source of mortality in the American population. The Western diet has been implicated as an important factor, though the mechanisms by which high levels of dietary sugar and fat contribute to heart failure remain controversial. Here, we use the fruit fly Drosophila to explore the role of diet on progressive heart failure. We show that elevated levels of dietary sugar are sufficient to direct progressive heart failure in flies including arrhythmia, reduced fractional shortening, and aspects of fibrosis. We demonstrate the importance of multiple cellular pathways, including the hexosamine biosynthetic pathway, as important for mediating these progressive defects, suggesting a potential avenue towards therapeutics.
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影响因子：
64.5
作者：
Böhni, R;Riesgo-Escovar, J;Hafen, E
通讯作者：
Hafen, E
影响因子：
9.2
作者：
Brogiolo, W;Stocker, H;Hafen, E
通讯作者：
Hafen, E
影响因子：
29
作者：
Birse RT;Choi J;Reardon K;Rodriguez J;Graham S;Diop S;Ocorr K;Bodmer R;Oldham S
通讯作者：
Oldham S
DOI：
10.1073/pnas.0601931103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Forsythe, Michele E.;Love, Dona C.;Hanover, John A.
通讯作者：
Hanover, John A.
影响因子：
9.3
作者：
BODMER, R
通讯作者：
BODMER, R