Docosahexaenoic acid (DHA) alleviates hepatic lipid accumulation by regulating mitochondrial quality control through ERK signaling pathway in grass carp (Ctenopharyngodon idellus)

Docosahexaenoic acid (DHA) alleviates hepatic lipid accumulation in fish, but the underlying mechanism re-mains unclear. Studies in mammals showed that promoting fatty acid (FA) beta-oxidation, which mainly occurs in mitochondrion, improves lipid accumulation. This study aims to investigate the effect of DHA on fatty acid (FA) beta-oxidation, focusing on the role of hepatic mitochondrial quality control (MQC) and mitochondrial function, in grass carp (Ctenopharyngodon idellus) in vivo and in vitro. Grass carps (41.87 +/- 0.08 g) were fed with diets supplemented with 0% (control) and 1% DHA for 8 weeks. Dietary 1% DHA markedly decreased the hep-atosomatic index, hepatic triglyceride (TG) content, and serum TG (P < 0.05). Dietary 1% DHA significantly increased ppar alpha and cpt1 mRNAs, which implies the activated FA beta-oxidation. In addition, dietary 1% DHA improved mitochondrial function by increasing the ATP content and antioxidant ability. The mRNAs encoding DRP1, OPA1, MFN1 and MFN2 were significantly increased by DHA (P < 0.05), suggesting that mitochondrial division and fusion were activated simultaneously. Transmission electron microscopy displayed that dietary 1% DHA triggers the increase of mitochondria. Along with this, mitochondrial DNA copy numbers and the mRNA expression of pgc1 alpha, tfam and nrf1 were significantly increased in 1% DHA group (P < 0.05), suggesting that DHA activated mitochondrial biogenesis. BNIP3/NIX-dependent mitophagy was also induced by DHA. Consistent with these in vivo results, DHA restored the loss of ATP content, mitochondrial membrane potential, and antioxidant ability in palmitic acid (PA)-treated hepatocytes in vitro, implying that DHA improved the MQC network damaged by PA. DHA further activated FA beta-oxidation and inhibited lipid accumulation in the hepatocytes. Importantly, U0126, an inhibitor of ERK, abrogated the effects of DHA on the MQC network and lipid meta-bolism. Taken together, the present study demonstrated that the alleviation of hepatic lipid accumulation by DHA is mediated by the activation of FA beta-oxidation and improvement of MQC via the ERK pathway. This study may shed light on the molecular mechanism underlying DHA's function in relieving hepatic lipid deposition in vertebrates.