A Mixture of Atropisomers Enhances Neutral Lipid Degradation in Mammalian Cells with Autophagy Induction.
A Mixture of Atropisomers Enhances Neutral Lipid Degradation in Mammalian Cells with Autophagy Induction.
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DOI：
10.1038/s41598-018-30679-0
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发表时间：
2018-08-14
影响因子：
4.6
通讯作者：
Tomoda H
中科院分区：
文献类型：
--
作者：
Kobayashi K;Ohte S;Ohshiro T;Ugaki N;Tomoda H
从嗜松篮状菌FKI-3864的真菌培养液中分离出具有联芳基二氢萘并吡喃酮结构的阻转异构体，地那品酮A1（DPA 1）（M位）和A2（DPA 2）（P位），作为中国仓鼠卵巢-K1（CHO-K1）细胞中[14 C]油酸合成[14 C]中性脂质（[14 C]三酰甘油（TG）和[14 C]胆固醇酯（CE））的抑制剂。DPA 2抑制[14 C]TG和[14 C]CE的合成（IC 50分别为0.65和5.6 μM），但DPA 1即使在12 μM时对[14 C]TG和[14 C]CE的合成也没有抑制活性。然而，DPA 1和DPA 2的1：1混合物（DPAmix）对[14 C]TG和[14 C]CE合成具有最强的抑制活性（IC 50分别为0.054和0.18 μM）。研究了DPAmix的作用机理。DPAmix对参与中性脂质合成的酶没有影响，而DPAmix增强了[14 C]中性脂质的降解，同时减少了CHO-K1细胞中积累的胞质脂滴。从自噬标志物蛋白的分析，DPAmix引起微管相关蛋白轻链3-II（LC 3-II）的剂量依赖性诱导和p62的降解。在使用巴弗洛霉素A1的自噬通量测定中，DPAmix上调自噬体周转。这些结果表明，DPAmix增强中性脂质降解以及诱导自噬。
Atropisomers with a biaryl dihydronaphthopyranone structure, dinapinones A1 (DPA1) (M position) and A2 (DPA2) (P position), were isolated from the fungus culture broth of Talaromyces pinophilus FKI-3864 as inhibitors of [14C]neutral lipid ([14C]triacylglycerol (TG) and [14C]cholesteryl ester (CE)) synthesis from [14C]oleic acid in Chinese hamster ovary-K1 (CHO-K1) cells. DPA2 inhibited [14C]TG and [14C]CE synthesis (IC50s, 0.65 and 5.6 μM, respectively), but DPA1 had no inhibitory activity on [14C]TG and [14C]CE synthesis even at 12 μM. However, a 1:1 mixture of DPA1 and DPA2 (DPAmix) had the most potent inhibitory activity on [14C]TG and [14C]CE synthesis (IC50s, 0.054 and 0.18 μM, respectively). The mechanism of action of DPAmix was investigated. DPAmix had no effects on the enzymes involved in neutral lipid synthesis, while DPAmix enhanced the degradation of [14C]neutral lipids with concomitant decrease in cytosolic lipid droplets accumulated in CHO-K1 cells. From analysis of autophagy marker proteins, DPAmix caused dose-dependent induction of microtubule-associated protein light chain 3-II (LC3-II) and degradation of p62. In the autophagic flux assay using bafilomycin A1, DPAmix upregulated autophagosome turnover. These results reveal that DPAmix enhances neutral lipid degradation together with induction of autophagy.
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影响因子：
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