Laboratorio de Fisiología Microbiana, Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000, Rosario, Argentina.
Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany.
Sci Rep. 2018 Apr 23;8(1):6398. doi: 10.1038/s41598-018-24925-8.
Proper cholesterol transport is crucial for the functionality of cells. In C. elegans, certain cholesterol derivatives called dafachronic acids (DAs) govern the entry into diapause. In their absence, worms form a developmentally arrested dauer larva. Thus, cholesterol transport to appropriate places for DA biosynthesis warrants the reproductive growth. Recently, we discovered a novel class of glycosphingolipids, PEGCs, required for cholesterol mobilization/transport from internal storage pools. Here, we identify other components involved in this process. We found that strains lacking polyunsaturated fatty acids (PUFAs) undergo increased dauer arrest when grown without cholesterol. This correlates with the depletion of the PUFA-derived endocannabinoids 2-arachidonoyl glycerol and anandamide. Feeding of these endocannabinoids inhibits dauer formation caused by PUFAs deficiency or impaired cholesterol trafficking (e.g. in Niemann-Pick C1 or DAF-7/TGF-β mutants). Moreover, in parallel to PEGCs, endocannabinoids abolish the arrest induced by cholesterol depletion. These findings reveal an unsuspected function of endocannabinoids in cholesterol trafficking regulation.
适当的胆固醇运输对于细胞的功能至关重要。在秀丽隐杆线虫中，某些胆固醇衍生物称为 dafachronic 酸（DAs），控制进入休眠状态。如果没有 DAs，线虫会形成发育停滞的 dauer 幼虫。因此，胆固醇运输到适当的地方进行 DAs 生物合成保证了生殖生长。最近，我们发现了一类新型糖鞘脂，即 PEGCs，它们是胆固醇从内部储存池动员/运输所必需的。在这里，我们鉴定了参与这个过程的其他成分。我们发现，缺乏多不饱和脂肪酸（PUFAs）的菌株在没有胆固醇的情况下生长时会经历更多的 dauer 停滞。这与多不饱和脂肪酸衍生的内源性大麻素 2-花生四烯酸甘油和大麻素酰胺的耗竭相关。这些内源性大麻素的喂养抑制了由 PUFAs 缺乏或胆固醇运输受损（例如在 Niemann-Pick C1 或 DAF-7/TGF-β 突变体中）引起的 dauer 形成。此外，与 PEGCs 平行，内源性大麻素消除了由胆固醇耗竭引起的阻滞。这些发现揭示了内源性大麻素在胆固醇运输调节中的一个意想不到的功能。
