Increased 4-hydroxynonenal formation contributes to obesity-related lipolytic activation in adipocytes.
Increased 4-hydroxynonenal formation contributes to obesity-related lipolytic activation in adipocytes.
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DOI：
10.1371/journal.pone.0070663
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Song Z
中科院分区：
文献类型：
--
作者：
Zhang X;Wang Z;Li J;Gu D;Li S;Shen C;Song Z
脂肪组织中的氧化应激在多种肥胖相关的代谢紊乱中起病因学作用。我们先前报道了脂肪组织4-羟基壬烯醛（4-HNE）含量的增加导致肥胖相关的小鼠血浆脂联素下降。在本研究中，我们研究了细胞内4-HNE积累对脂肪细胞/脂肪组织脂解反应的影响及其机制。在完全分化的3 T3-L1和原代脂肪细胞中，在基础和异丙肾上腺素刺激的条件下，5小时的4-HNE暴露以剂量依赖性方式升高脂解反应，证明甘油和脂肪酸释放显著增加。使用切碎的人内脏脂肪组织时的可比观察结果证实了这一结论。机制研究表明，4-HNE刺激的脂解激活是多因素的。4-HNE暴露迅速增加细胞内cAMP（cAMP）水平，这是伴随着蛋白激酶A（PKA）及其直接下游靶标激素敏感脂肪酶（HSL）的磷酸化增加。与H89，一种有效的PKA抑制剂，预孵育，阻止4-HNE刺激的甘油释放，表明增强的脂解作用，响应于4-HNE增加，主要是由cAMP/PKA信号通路在脂肪细胞介导的。除了激活cAMP/PKA/HSL途径之外，4-HNE暴露还抑制AMP活化蛋白激酶（AMPK），这是一种脂解的抑制途径，通过蛋白质印迹法测定AMPK的磷酸化形式和ELISA测定酶活性。此外，药理学AMPK激活剂5-氨基咪唑-4-甲酰胺1-β-D-呋喃核糖苷（AICAR）减轻4-HNE诱导的脂解，表明AMPK抑制也有助于4-HNE引起的脂解反应。总之，我们的研究结果表明，脂肪细胞/脂肪组织中细胞内4-HNE积累的增加有助于肥胖相关的脂解激活。
Oxidative stress in adipose tissue plays an etiological role in a variety of obesity-related metabolic disorders. We previously reported that increased adipose tissue 4-hydroxynonenal (4-HNE) contents contributed to obesity-related plasma adiponectin decline in mice. In the present study, we investigated the effects of intracellular 4-HNE accumulation on lipolytic response in adipocytes/adipose tissues and underlying mechanisms. In both fully-differentiated 3T3-L1 and primary adipocytes, a 5-hour 4-HNE exposure elevated lipolytic reaction in a dose-dependent manner at both basal and isoproterenol-stimulated conditions, evidenced by significantly increased glycerol and fatty acids releases. This conclusion was corroborated by the comparable observations when the minced human visceral adipose tissues were used. Mechanistic investigations revealed that 4-HNE-stimulated lipolytic activation is multifactorial. 4-HNE exposure quickly increased intracellular cyclic AMP (cAMP) level, which was concomitant with increased phosphorylations of protein kinase A (PKA) and its direct downstream target, hormone sensitive lipase (HSL). Pre-incubation with H89, a potent PKA inhibitor, prevented 4-HNE stimulated glycerol release, suggesting that enhanced lipolytic action in response to 4-HNE increase is mediated mainly by cAMP/PKA signal pathway in adipocytes. In addition to activating cAMP/PKA/HSL pathway, 4-HNE exposure also suppresses AMP-activated protein kinase (AMPK), a suppressive pathway for lipolysis, measured by both Western blotting for phosphorylated form of AMPK and ELISA for enzyme activity. Furthermore, 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), a pharmacological AMPK activator, alleviated 4-HNE-induced lipolysis, suggesting that AMPK suppression also contributes to 4-HNE elicited lipolytic response. In conclusion, our findings indicate that increased intracellular 4-HNE accumulation in adipocytes/adipose tissues contributes to obesity-related lipolytic activation.
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