Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipids and energy homeostasis in the cell. LDs can grow through either local lipid synthesis or LD fusion. However, how lipids involving in LD fusion for LD growth is largely unknown. Here, we show that genetic mutation of acox-3 (acyl-CoA oxidase), maoc-1 (enoyl-CoA hydratase), dhs-28 (3-hydroxylacyl-CoA dehydrogenase), and daf-22 (3-ketoacyl-CoA thiolase), all involved in the peroxisomal β-oxidation pathway in Caenorhabditis elegans, led to rapid fusion of adjacent LDs to form giant LDs (gLDs). Mechanistically, we show that dysfunction of peroxisomal β-oxidation results in the accumulation of long-chain fatty acid-CoA and phosphocholine, which may activate the sterol-binding protein 1/sterol regulatory element–binding protein to promote gLD formation. Furthermore, we found that inactivation of either FAT-2 (delta-12 desaturase) or FAT-3 and FAT-1 (delta-15 desaturase and delta-6 desaturase, respectively) to block the biosynthesis of polyunsaturated fatty acids (PUFAs) with three or more double bonds (n≥3-PUFAs) fully repressed the formation of gLDs; in contrast, dietary supplementation of n≥3-PUFAs or phosphocholine bearing these PUFAs led to recovery of the formation of gLDs in peroxisomal β-oxidation–defective worms lacking PUFA biosynthesis. Thus, we conclude that n≥3-PUFAs, distinct from other well-known lipids and proteins, promote rapid LD fusion leading to LD growth.

脂滴（LD）是动态调节细胞内脂质和能量稳态的细胞内细胞器。 LD 可以通过局部脂质合成或 LD 融合来生长。然而，脂质如何参与 LD 融合以促进 LD 生长尚不清楚。在这里，我们展示了acox-3 （酰基辅酶A氧化酶）、 maoc-1 （烯酰基辅酶A水合酶）、 dhs-28 （3-羟酰辅酶A脱氢酶）和daf-22 （3-酮脂酰辅酶A）的基因突变硫解酶）均参与秀丽隐杆线虫的过氧化物酶体 β-氧化途径，导致相邻 LD 快速融合形成巨型 LD（gLD）。从机制上讲，我们发现过氧化物酶体β-氧化功能障碍会导致长链脂肪酸CoA和磷酸胆碱的积累，这可能会激活甾醇结合蛋白1/甾醇调节元件结合蛋白以促进gLD的形成。此外，我们发现 FAT-2（delta-12 去饱和酶）或 FAT-3 和 FAT-1（分别为 delta-15 去饱和酶和 delta-6 去饱和酶）的失活可阻断多不饱和脂肪酸 (PUFA) 的生物合成三个或更多双键（n≥3-PUFA）完全抑制gLD的形成；相比之下，膳食补充n≥3-PUFA或含有这些PUFA的磷酸胆碱导致缺乏PUFA生物合成的过氧化物酶体β-氧化缺陷线虫中gLD的形成恢复。因此，我们得出结论，与其他众所周知的脂质和蛋白质不同，n≥3-PUFA 促进 LD 快速融合，导致 LD 生长。