來自華中農業(yè)大學生命技術學院和德國糖尿病中心的研究人員在新研究中揭示了脂肪細胞分泌因子抵抗素(Resistin)誘導肝脂肪變性的分子機制,，相關論文于1月25日發(fā)表在國際著名肝臟疾病雜志Hepatology（最新影響因子11.665）上。
領導這一研究的是華中農業(yè)大學生命技術學院的楊在清（Zaiqing Yang）教授,，其主要研究方向包括脂肪細胞因子,，脂肪沉積的分子機理，脂肪細胞分化與代謝,，脂肪細胞功能基因組以及動物基因的表達調控與信號傳導,。學術刊物上發(fā)表學術論文80余篇。
肥胖是現(xiàn)代工業(yè)社會的一種流行病,，它導致胰島素,、糖和血脂的血液水平的混亂,，而這些問題又會引發(fā)高血壓、Ⅱ型糖尿病和脂肪肝,。肥胖還能增加不同類型癌癥的風險。目前,，越來越多的人們受到肥胖及相關的慢性疾病的困擾,。然而到目前為止，對于肥胖導致糖尿病,、脂肪肝和血脂問題的分子機制仍了解甚少,，闡明這些過程的確切機制對于預防及改善這些疾病的治療具有重要的意義。
Resistin是抵抗素樣分子家族成員之一,，是由脂肪細胞分泌的,、富含半胱氨酸的細胞因子。研究人員曾證實,，嚙齒類動物體內的resistin有誘導胰島素抵抗的作用,。近來，越來越多的研究表明resistin與肥胖,、胰島素抵抗,、2型糖尿病、心血管疾病等機體多種疾病相關,。
在這篇新文章中,，研究人員通過小鼠實驗發(fā)現(xiàn)：Resistin下調了線粒體的數(shù)量和活性，促進了肝脂肪變性,，誘導了胰島素抵抗（IR）,。這一時間進程表明，在脂肪沉積改變及胰島素抵抗形成前便已有線粒體數(shù)量改變,。當線粒體數(shù)量穩(wěn)定之時,，Resistin不會刺激肝脂肪沉積。采用突變研究,，研究人員證實核因子κB（NF-κB）p65亞基的Thr464殘基對線粒體調控至關重要,。鄰位連接分析(proximity ligation assay , PLA)結果揭示，resistin通過促進p65和PGC-1α互作,，導致了PGC-1α失活以及線粒體數(shù)量減少,。信號轉導分析證實Resistin通過新的PKC-PKG-p65-PGC-1α信號下調了線粒體。
研究結果表明Resistin通過減少線粒體數(shù)量誘導了肝脂肪變性,。新研究揭示了線粒體調控的一條新信號通路,，表明維持正常線粒體含量有可能是肥胖相關疾病的一種新治療策略。(生物谷Bioon.com)
DOI: 10.1002/hep.26167
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PMID:
Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway
Lei Zhou1,*, Xiaolan Yu1, Qingjie Meng1,Hongqiang Li1, Congcong Niu1, Yun Jiang1, Yuxi Cai1, Minghui Li1, Qiang Li1, Chaoqiang An1, Le Shu1, Ao Chen1, Handong Su1, Yin Tang1, Shen Yin1, Silja Raschke2, Kristin Eckardt2, Jürgen Eckel2, Zaiqing Yang1,‡,
Obesity is associated with many severe chronic diseases and deciphering its development and molecular mechanisms is necessary for promoting treatment. Previous studies have revealed that mitochondrial content is down-regulated in obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) and proposed that NAFLD and diabetes are mitochondrial diseases. However, the exact mechanisms underlying these processes remain unclear. In this study, we discovered that resistin down-regulated the content and activities of mitochondria, enhanced hepatic steatosis, and induced insulin resistance (IR) in mice. The time course indicated that the change in mitochondrial content was before the change in fat accumulation and development of insulin resistance. When the mitochondrial content was maintained, resistin did not stimulate hepatic fat accumulation. The present mutation study found that the residue Thr464 of the p65 subunit of nuclear factor kappa B was essential for regulating mitochondria. A proximity ligation assay revealed that resistin inactivated peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) and diminished the mitochondrial content by promoting the interaction of p65 and PGC-1α. Signaling-transduction analysis demonstrated that resistin down-regulated mitochondria by a novel protein kinase C/protein kinase G/p65/PGC-1α-signaling pathway. Conclusion: Resistin induces hepatic steatosis through diminishing mitochondrial content. This reveals a novel pathway for mitochondrial regulation, and suggests that the maintenance of normal mitochondrial content could be a new strategy for treatment of obesity-associated diseases.
