An intestinal DHA-PA-PG axis promotes digestive organ expansion by mediating usage of maternally-deposited yolk lipids

Abstract Although the metabolism of yolk lipids such as docosahexaenoic acid (DHA) is known to play important roles in embryonic development, the underlying mechanism remains unclear. Here we found that the zebrafish hsd17b12a, which encodes an intestinal epithelial-specific enzyme, is crucial for the biosynthesis of long-chain fatty acids (LCFAs) in primitive intestine of larval fish. The deficiency of hsd17b12a leads to severe developmental defects in the primitive intestine and exocrine pancreas. Mechanically, hsd17b12a deficiency interrupts DHA synthesis from essential fatty acids (EFAs) derived from yolk-deposited triglycerides (TAGs), and consequently disrupts an intestinal DHA-phosphatidic acid (PA)-phosphatidylglycerol (PG) axis. This ultimately results in developmental defects of digestive organs, primarily driven by ferroptosis. Our findings indicate that the DHA-PA-PG axis in the primitive intestine facilitates the uptake of yolk lipids and promotes the expansion of digestive organs, thereby uncovering a novel mechanism through which DHA regulates embryonic development.