# Simvastatin Improves the High-Fat-Diet-Induced Metabolic Disorder in Juvenile Chinese Giant Salamander (Andrias davidianus) Through Inhibiting Endoplasmic Reticulum Stress and Enhancing Mitochondrial Function

## TL;DR

Simvastatin helps reduce liver damage and metabolic issues in Chinese giant salamanders caused by high-fat diets by reducing endoplasmic reticulum stress and improving mitochondrial function.

## Contribution

This study identifies simvastatin as an effective nutritional intervention for high-fat-diet-induced metabolic disorders in Chinese giant salamanders.

## Key findings

- Simvastatin alleviates liver damage and hyperlipidemia in high-fat-diet-fed salamanders.
- Simvastatin reduces endoplasmic reticulum stress and improves mitochondrial function.
- High-fat diets cause metabolic disorders, but simvastatin intervention mitigates these effects.

## Abstract

Chinese giant salamander (Andrias davidianus), an emerging aquatic economic species, frequently exhibits metabolic disorders in practical culture due to the adoption of formulated feed. To date the underlying mechanisms are still poorly elucidated with the nutritional interventions poorly developed. As feeding a high-fat diet is a well-established approach for modeling metabolic disorders, we first evaluated the optimal dietary lipid requirement (95.16–101.02 g/kg) of A. davidianus based on growth performance. Subsequently, a high-fat-diet (149.2 g/kg lipid)-induced metabolic disorder model was established. Meanwhile, given its established lipid-lowering properties, simvastatin was used as a nutritional intervention to alleviate the metabolic disorders. As a result, simvastatin supplementation effectively alleviated the liver damage and hyperlipidemia of A. davidianus fed a high-fat diet by inhibiting endoplasmic reticulum stress and enhancing mitochondrial function. Our findings partly unveil the pathological basis of the metabolic disorders in A. davidianus and provide new insights for the prevention and cure of it.

In order to deeply understand the potential mechanisms underlying the metabolic disorders of Chinese giant salamander (Andrias davidianus), a total of two feeding trials were conducted in the present study. For experiment I, the diets containing five graded levels of lipids at 32.8, 58.7, 87.9, 122.4, and 149.2 g/kg were formulated, respectively, and fed to juvenile A. davidianus for 90 days. The quadratic regression analysis based on growth performance results indicated that the optimal dietary lipid level is 95.16–101.02 g/kg. Meanwhile, a dietary lipid level of 149.2 g/kg was found to reduce the growth performance of A. davidianus. Based on this, in experiment II, a normal-fat diet (86.8 g/kg crude lipid), a high-fat diet (HFD, 148.4 g/kg crude lipid), and an HFD supplemented with 0.1 g/kg simvastatin were prepared, respectively, and fed to the juveniles for 90 days. The results indicated that HFD feeding resulted in hyperlipidemia, hepatic damage, endoplasmic reticulum stress, and mitochondrial dysfunction, while simvastatin administration alleviated these symptoms. In conclusion, simvastatin could alleviate the HFD-induced metabolic disorders in A. davidianus, as may be achieved by inhibiting ER stress and enhancing mitochondrial function.