FXR, a Key Regulator of Lipid Metabolism, Is Inhibited by ER Stress-Mediated Activation of JNK and p38 MAPK in Large Yellow Croakers (Larimichthys crocea) Fed High Fat Diets.

Jianlong Du,Junzhi Zhang,Wei Fang,Wei Xu,Kangsen Mai,Dan Xu,Qinghui Ai,Xiaojun Xiang

doi:10.3390/nu13124343

Abstract

High-fat diets induced abnormal lipid accumulation in the liver of cultured fish that caused body damage and diseases. The purpose of this research was to investigate the role and mechanism of farnesoid X receptor (FXR) in regulating lipid metabolism and to determine how high-fat diets affect FXR expression in large yellow croakers. The results showed that ligand-meditated FXR-activation could prevent abnormal lipid accumulation in the liver and hepatocytes of large yellow croakers. FXR activation increased the expression of lipid catabolism-related genes while decreasing the expression of lipogenesis-related genes. Further investigation found that the promoter activity of proliferator-activated receptor α (PPARα) could be increased by croaker FXR. Through the influence of SHP on LXR, FXR indirectly decreased the promoter activity of sterol regulatory element binding protein 1 (SREBP1) in large yellow croakers. Furthermore, the findings revealed that endoplasmic reticulum (ER)-stress-induced-activation of JNK and P38 MAPK participated in the reduction of FXR induced by high-fat diets. Then, hepatocyte nuclear factor 1α (HNF1α) was confirmed to be an FXR regulator in large yellow croaker, and it was reduced by high-fat diets and ER stress. In addition, co-expression of c-Jun with HNF1α inhibited the effect of HNF1α on FXR promoter, and suppression of P38 MAPK could relieve the HNF1α expression reduction caused by ER stress activation. In summary, the present study showed that FXR mediated lipid metabolism can prevent abnormal lipid accumulation through regulating PPARα and SREBP1 in large yellow croakers, while high-fat diets can suppress FXR expression by ER stress mediated-activation of JNK and P38 MAPK pathways. This research could benefit the study of FXR functions in vertebrate evolution and the development of therapy or preventative methods for nutrition-related disorders.

Highlights

High-fat diets (HFDs) have become increasingly common in aquaculture
The results showed that high-fat diets significantly enhanced the mRNA level of lipogenesis related gene (p < 0.05)
The results showed that feeding an high-fat diet (HFD) and FA treatment decreased expression of lipid catabolism related genes and increased expression of lipogenesisrelated genes

Summary

Introduction

High-fat diets (HFDs) have become increasingly common in aquaculture. Excessive fat intake leads to abnormal lipid deposition in cultured fish liver, which may cause body damage, diseases and result in retarded growth. The issue of excessive lipid accumulation in the liver is present in nonalcoholic fatty liver disease (NALFD) [1]. On the basis of googd understanding of the functions of metabolic genes, various metabolic targets have been studied and used for regulating lipid metabolism and treatment of NALFD [2]. The understanding of the mechanism of lipid metabolism and the roles of genes in fish is still limited. There is an urgent need to investigate the metabolic process and develop solutions for managing lipid deposition in fish

Objectives

Methods

Conclusion