Loss of dmrt2a Alters Hepatic LC-PUFA Composition and Lipid Homeostasis in Zebrafish

Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutrients for human health, and fish and aquatic products are the primary dietary sources of these bioactive lipids. The endogenous capacity of teleosts to synthesize LC-PUFAs directly determines their nutritional value for human consumers. However, the genetic regulators governing this biosynthetic pathway remain largely unexplored. Here, we show that targeted disruption of dmrt2a, a transcription factor gene, in zebrafish (Danio rerio) via CRISPR/Cas9, alters hepatic LC-PUFA composition and lipid homeostasis. Homozygous dmrt2a^-/- mutants exhibited significantly reduced molar percentages of EPA (C20:5n-3) and DHA (C22:6n-3) in the liver, accompanied by the accumulation of their precursors, C18:2n-6 and C18:3n-3. In addition, the mutants developed a hepatic lipid metabolic disorder characterized by pathological accumulation of lipid droplets and elevated triglyceride levels, thereby providing a novel zebrafish model for research on hepatic steatosis. Transcriptomic profiling revealed that differentially expressed genes between dmrt2a^-/- mutant and wild-type livers were significantly enriched in fatty acid biosynthesis and metabolic pathways. Notably, an LC-PUFA-enriched diet partially rescued the aberrant hepatic lipid phenotype. To our knowledge, this is the first study in any fish species to link a DMRT-family transcription factor to hepatic LC-PUFA composition and lipid homeostasis, suggesting dmrt2a as a potential target for genetic breeding to improve the nutritional quality of aquaculture products.