Palanker Laura, Tennessen Jason M, Lam Geanette, Thummel Carl S
Department of Human Genetics, University of Utah School of Medicine, 15 North 2030 East Room 2100, Salt Lake City, UT 84112-5330, USA.
Cell Metab. 2009 Mar;9(3):228-39. doi: 10.1016/j.cmet.2009.01.009.
Drosophila HNF4 (dHNF4) is the single ancestral ortholog of a highly conserved subfamily of nuclear receptors that includes two mammalian receptors, HNFalpha and HNFgamma, and 269 members in C. elegans. We show here that dHNF4 null mutant larvae are sensitive to starvation. Starved mutant larvae consume glycogen normally but retain lipids in their midgut and fat body and have increased levels of long-chain fatty acids, suggesting that they are unable to efficiently mobilize stored fat for energy. Microarray studies support this model, indicating reduced expression of genes that control lipid catabolism and beta-oxidation. A GAL4-dHNF4;UAS-lacZ ligand sensor can be activated by starvation or exogenous long-chain fatty acids, suggesting that dHNF4 is responsive to dietary signals. Taken together, our results support a feed-forward model for dHNF4, in which fatty acids released from triglycerides activate the receptor, inducing enzymes that drive fatty acid oxidation for energy production.
果蝇肝细胞核因子4（dHNF4）是核受体高度保守亚家族的唯一祖先直系同源物，该亚家族包括两种哺乳动物受体，即肝细胞核因子α（HNFα）和肝细胞核因子γ（HNFγ），以及秀丽隐杆线虫中的269个成员。我们在此表明，dHNF4基因敲除突变体幼虫对饥饿敏感。饥饿的突变体幼虫能正常消耗糖原，但在中肠和脂肪体中保留脂质，且长链脂肪酸水平升高，这表明它们无法有效地动员储存的脂肪来获取能量。微阵列研究支持这一模型，表明控制脂质分解代谢和β氧化的基因表达降低。一种GAL4-dHNF4；UAS-lacZ配体传感器可被饥饿或外源性长链脂肪酸激活，这表明dHNF4对饮食信号有反应。综上所述，我们的结果支持dHNF4的前馈模型，其中甘油三酯释放的脂肪酸激活受体，诱导驱动脂肪酸氧化以产生能量的酶。
