A Mixture of Atropisomers Enhances Neutral Lipid Degradation in Mammalian Cells with Autophagy Induction.

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.