# Itaconic Acid Activates Lysosomal Biogenesis and Autophagy Flux and Mitigates High-Fat Diet-Induced Liver Lipid Accumulation in Largemouth Bass (Micropterus salmoides)

## TL;DR

Itaconic acid reduces liver fat in fish fed a high-fat diet by boosting autophagy and lysosomal activity.

## Contribution

This study reveals that itaconic acid activates autophagy and lysosomal biogenesis to mitigate lipid accumulation in fish livers.

## Key findings

- ITA improved growth performance and reduced lipid accumulation in fish livers.
- ITA enhanced fatty acid oxidation and reduced lipid esterification through metabolomic changes.
- ITA activated the AMPK/mTOR pathway and upregulated autophagy and lysosomal genes.

## Abstract

This study investigated the interventional effects of dietary itaconic acid (ITA) on high-fat diet (HFD)-induced lipid deposition in largemouth bass (Micropterus salmoides) and the underlying mechanisms. Results showed that ITA supplementation significantly alleviated HFD-induced growth performance inhibition, as indicated by increased weight gain rate, increased specific growth rate, and reduced feed conversion ratio. ITA supplementation effectively reversed the HFD-induced increase in the hepatosomatic index, intraperitoneal fat ratio, serum triglycerides, total cholesterol, low-density lipoprotein/high-density lipoprotein ratio, hepatic lipid droplet accumulation, and hepatocyte vacuolation. Importantly, ITA ameliorated HFD-induced impairment of antioxidant capacity and reduced liver alanine aminotransferase and aspartate aminotransferase activities. Liver metabolomics revealed that ITA reduced levels of 20 fatty acids, 14 acylcarnitines, and 13 glycerides, suggesting enhanced fatty acid oxidation and reduced lipid esterification. Transcriptome sequencing and q-PCR validation demonstrated that ITA activated the AMPK/mTOR pathway, upregulating autophagy-related genes (prkaa1, ulk2, map1lc3a, sqstm1) and lysosomal biogenesis-related genes (ap3s2, igf2r, lgmn, ctso), thereby enhancing autophagic-lysosomal flux and promoting lipid degradation. In conclusion, ITA reduces hepatic lipid accumulation by synergistically activating autophagy and lysosomal biogenesis, thereby facilitating the oxidative degradation of fatty acids within lysosomes. This study provides a theoretical basis for the application of ITA as a functional feed additive in aquaculture.