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A Mixture of Atropisomers Enhances Neutral Lipid Degradation in Mammalian Cells with Autophagy Induction
Description
<jats:title>Abstract</jats:title><jats:p>Atropisomers with a biaryl dihydronaphthopyranone structure, dinapinones A1 (DPA1) (<jats:italic>M</jats:italic> position) and A2 (DPA2) (<jats:italic>P</jats:italic> position), were isolated from the fungus culture broth of <jats:italic>Talaromyces pinophilus</jats:italic> FKI-3864 as inhibitors of [<jats:sup>14</jats:sup>C]neutral lipid ([<jats:sup>14</jats:sup>C]triacylglycerol (TG) and [<jats:sup>14</jats:sup>C]cholesteryl ester (CE)) synthesis from [<jats:sup>14</jats:sup>C]oleic acid in Chinese hamster ovary-K1 (CHO-K1) cells. DPA2 inhibited [<jats:sup>14</jats:sup>C]TG and [<jats:sup>14</jats:sup>C]CE synthesis (IC<jats:sub>50</jats:sub>s<jats:sub>,</jats:sub> 0.65 and 5.6 μM, respectively), but DPA1 had no inhibitory activity on [<jats:sup>14</jats:sup>C]TG and [<jats:sup>14</jats:sup>C]CE synthesis even at 12 μM. However, a 1:1 mixture of DPA1 and DPA2 (DPA<jats:sub>mix</jats:sub>) had the most potent inhibitory activity on [<jats:sup>14</jats:sup>C]TG and [<jats:sup>14</jats:sup>C]CE synthesis (IC<jats:sub>50</jats:sub>s, 0.054 and 0.18 μM, respectively). The mechanism of action of DPA<jats:sub>mix</jats:sub> was investigated. DPA<jats:sub>mix</jats:sub> had no effects on the enzymes involved in neutral lipid synthesis, while DPA<jats:sub>mix</jats:sub> enhanced the degradation of [<jats:sup>14</jats:sup>C]neutral lipids with concomitant decrease in cytosolic lipid droplets accumulated in CHO-K1 cells. From analysis of autophagy marker proteins, DPA<jats:sub>mix</jats:sub> 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 A<jats:sub>1</jats:sub>, DPA<jats:sub>mix</jats:sub> upregulated autophagosome turnover. These results reveal that DPA<jats:sub>mix</jats:sub> enhances neutral lipid degradation together with induction of autophagy.</jats:p>
Journal
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- Scientific Reports
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Scientific Reports 8 (1), 12099-, 2018-08-14
Springer Science and Business Media LLC