Laboratory of Metabolic Genetics, College of Life Sciences, Capital Normal University, Beijing 100048, China.
Laboratory of Metabolic Genetics, College of Life Sciences, Capital Normal University, Beijing 100048, China
Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8841-8846. doi: 10.1073/pnas.1704277114. Epub 2017 Jul 31.
Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12-dependent manner. Human CYP4V2 can substitute for CYP-37A1 in This finding suggests the existence of a conserved CYP4V2-POR-nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.
核受体在调节人类脂肪代谢和能量产生方面发挥着重要作用。然而，许多核受体的调节功能和内源性配体仍未被确定。在这里，我们报告 CYP-37A1（与人细胞色素 P450 CYP4V2 的同源物）、EMB-8（与人 P450 氧化还原酶 POR 的同源物）和 DAF-12（与人核受体 VDR/LXR 的同源物）构成了激素合成和核受体途径。该途径特异性调节脂肪储存脂质滴的热敏融合。CYP-37A1 与 EMB-8 一起合成一种亲脂性激素，与 Δ7-dafachronic acid 不同，它抑制 DAF-12 的融合促进功能。CYP-37A1 还以 DAF-12 依赖的方式负调节高温下的热耐受性和寿命。人细胞色素 P4V2 可以替代 CYP-37A1 在这一发现表明存在保守的 CYP4V2-POR-核受体途径，该途径在将多房脂质滴转化为人类细胞中的单房脂质滴中起作用；该途径的失调可能导致病理性脂肪储存。
