肝脏糖代谢稳态失衡在糖尿病发生过程中起决定性作用。我们发现花生四烯酸ω-氧化酶(cyp4a)家族、FAM3新基因家族和生物钟转录因子Bmal1和Clock的表达及功能异常与肝脏胰岛素抵抗和肝脏糖代谢失衡直接相关，提示这些基因可能参与肝脏胰岛素敏感性的调节。本课题拟重点研究：1）Cyp4a10/4a14、FAM3A/3B在肝脏糖代谢调控中的作用及机制，以及它们的相互作用对调节肝脏胰岛素信号通路及胰岛素敏感性的影响；2）代谢性核受体PPARs、LXRs、NR2F2及转录因子FOXO1对Cyp4a和FAM3家族的转录调控作用及机制；3）非编码RNA对Cyp4a和FAM3家族基因的转录后调控作用；4）分子生物钟转录因子Bmal1和Clock调控糖代谢网络的作用及机制。本课题的开展将有助于揭示这些新基因在糖代谢调控中的作用及机制，也对全面阐明糖代谢稳态维持和失衡及糖尿病发生的机制有重要价值。

Impaired glucose homeostasis in the liver plays a crucial role in the pathogenesis of diabetes. We have recently found that arachidonic acid omega-oxygenase cytochrome P450 4A (Cyp4a) family including Cyp4a10 and Cyp4a14，newly identified FAM3 gene family member FAM3A and FAM3B (PANDER)，and clock gene family including Bmal1 and Clock may play important roles in maintaining glucose homeostasis. Dysregulation of these genes in the liver was highly associated with the levels of hepatic insulin resistance and hyperglycemia. The current project aimed to study: 1) the roles and mechanisms of Cyp4a10,Cyp4a14, FAM3A, FAM3B, Clock and Bmal1 in the regulation of hepatic glucose metabolism. The impact of functional crosstalk between members within each family on insulin signaling pathway in the liver will be also addressed; 2) transcriptional regulation of Cyp4a10, Cyp4a14, FAM3A and FAM3B in liver and other tissues by metabolic nuclear receptors PPARs, LXRs and NR2F2 and transcription factor FOXO1; 3) post-transcriptional regulation of Cyp4a10, Cyp4a14, FAM3A, FAM3B, Clock and Bmal1 genes by non-coding micro-RNA (miRNAs); 4) Clock genes-controlled target gene network and its role in glucose homeostasis regulation. The completion of these studies will shed light on our understanding of the mechanisms involved in the pathogenesis of impaired glucose homeostasis and diabetes.