4-HNE在肥胖相关胰岛素抵抗形成和发展中的作用和分子机制

The World Health Organization (WHO) warned that obesity is the world's fifth-largest cause of death risk. Obese patients have varying degrees of insulin resistance (insulin resistance, IR). Mechanism of obesity-induced IR has become a hot topic in recent endocrinology research. Obesity is often accompanied by increased oxidative stress level, and 4-HNE（4-hydroxynonenal）is the representative product of oxidative stress. Now a growing number of studies suggest that adipose tissue is the primary site of IR. Especially, visceral adipose tissue plays a very important role in the development process of IR and metabolic syndrome. The existing experimental data show that 4-HNE promotes lipolysis in adipocytes, inhibits the anti-inflammatory cytokine secretion, which is closely related with IR. Autophagic abnormalities play an important role in the occurrence of metabolic abnormalities diseases. The mechanisms by which 4-HNE modified autophagy causes IR, has so far not been reported at home and abroad. Our team through the study of 4-HNE, reveals the mechanisms that 4-HNE by causing inflammation, abnormal autophagy cause the occurrence and development of the IR, not only to fill the research gaps at home and abroad, but also to supply new theories and new drug targets for effective prevention and treatment of IR.

世界卫生组织警告称，肥胖是全球引起死亡的第五大风险因素。肥胖患者均不同程度地存在胰岛素抵抗（insulin resistance, IR)。肥胖引起IR的机制已成为近期内分泌学研究的一个热点。肥胖往往伴随体内氧化应激水平的升高，4-羟基壬烯醛（4-hydroxynonenal，4-HNE）是其代表性产物。研究表明脂肪组织是IR产生的始发部位，尤其是内脏脂肪组织在IR和代谢综合征发生、发展过程中起着非常重要的作用。我们已有的实验数据表明，4-HNE促进脂肪细胞发生脂解，抑制抗炎因子分泌，与IR发生密切相关。自噬异常在代谢异常性疾病的发生中发挥了重要作用，有关于4-HNE通过调节自噬引起IR的机制，迄今为止国内外尚无报道。我们小组通过开展4-HNE的研究，揭示4-HNE通过引发炎症、异常自噬引起IR发生发展的机制，这填补了国内外的研究空白，为IR的有效防治提供新的理论依据和药物作用新靶点。

有文献报道，肥胖是全球引起死亡的第五大风险因素，并且肥胖患者均不同程度地存在胰岛素抵抗（insulin resistance,IR)。肥胖往往伴随体内氧化应激水平的升高，4-羟基壬烯醛（4-hydroxynonenal，4-HNE）是其代表性产物。脂肪组织在IR和代谢综合征发生、发展过程中起着非常重要的作用。我们已有的实验数据表明，4-HNE促进脂肪细胞发生脂解，抑制抗炎因子分泌，与IR发生密切相关。自噬异常在代谢异常性疾病的发生中发挥了重要作用，有关于4-HNE通过调节自噬引起IR的机制，迄今为止国内外尚无报道。因此，我们开展对4-HNE的研究，研究发现4-HNE 与leptin分泌呈现正相关，与adiponectin分泌和胰岛素敏感性呈现负相关；4-HNE作用能够降低脂肪细胞中adiponectin的分泌水平，同时4-HNE促进自噬；应用生物信息学的方法，检测到23条参与肥胖相关炎症的miRNA-TF-gene调控通路；实验证实4-HNE通过抑制miR-29b→SP1→TNF-a通路和促进ETS1→TNF-a通路增加TNF-a基因转录。本研究将补充和完善4-HNE引起IR的发病机制，为IR的有效防治提供新的理论依据和药物作用新靶点。