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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.

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.

SUBMITTER: Du J

PROVIDER: S-EPMC8706856 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Chemosensory receptors, which are all G-protein-coupled receptors (GPCRs), come in four types: odorant receptors (ORs), vomeronasal receptors, trace-amine associated receptors and formyl peptide receptor-like proteins. The ORs are the most important receptors for detecting a wide range of environmental chemicals in daily life. Most fish OR genes have been identified from genome databases following the completion of the genome sequencing projects of many fishes. However, it remains unclear whether these OR genes from the genome databases are actually expressed in the fish olfactory epithelium. Thus, it is necessary to clone the OR mRNAs directly from the olfactory epithelium and to examine their expression status. RESULTS: Eighty-nine full-length and 22 partial OR cDNA sequences were isolated from the olfactory epithelium of the large yellow croaker, Larimichthys crocea. Bayesian phylogenetic analysis classified the vertebrate OR genes into two types, with several clades within each type, and showed that the L. crocea OR genes of each type are more closely related to those of fugu, pufferfish and stickleback than they are to those of medaka, zebrafish and frog. The reconciled tree showed 178 duplications and 129 losses. The evolutionary relationships among OR genes in these fishes accords with their evolutionary history. The fish OR genes have experienced functional divergence, and the different clades of OR genes have evolved different functions. The result of real-time PCR shows that different clades of ORs have distinct expression levels. CONCLUSION: We have shown about 100 OR genes to be expressed in the olfactory epithelial tissues of L. crocea. The OR genes of modern fishes duplicated from their common ancestor, and were expanded over evolutionary time. The OR genes of L. crocea are closely related to those of fugu, pufferfish and stickleback, which is consistent with its evolutionary position. The different expression levels of OR genes of large yellow croaker may suggest varying roles of ORs in olfactory function.

Dataset Information

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.

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