Activated farnesoid X receptor alleviates lipid metabolism disorder and cell stress induced by high glucose in turbot (Scophthalmus maximus)

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The function of farnesoid X receptor (FXR) in glucose and lipid metabolism in turbot (Scophthalmus maximus) was investigated in vitro and in vivo. Hepatic lipid deposition was detected in the HG-I group (25% carbohydrate diet), and intracellular lipid droplets increased significantly relative to those in the CON-I group (16% carbohydrate diet), and this effect was alleviated in the HG-I-G group (25% carbohydrate diet with FXR activation). High glucose (50 mM) conditions significantly up-regulated the expression of lipid synthesis-related genes and increased fatty acid synthetase (FASN) protein levels in primary liver cells of turbot, and this up-regulation was subsequently weakened by FXR activation, consistent with the in vivo results. Moreover, FXR was found to directly bind to the FASN promoter, thereby suppressing its transcriptional activity. Knockdown of the small heterodimer partner (SHP), a key target of FXR, weakened the regulation of lipid metabolism by altering the expression of sterol regulatory element-binding protein-1c (SREBP-1c) associated with lipid homeostasis. In addition, compared with the CON-I group, the HG-I group exhibited disordered organelle distribution, marked lipid droplet deposition, and fragmentation and dispersion of the rough endoplasmic reticulum (ER). In contrast, in the HG-I-G group, FXR activation significantly alleviated lipid droplet deposition and restored the normal morphology of the rough ER. The results of autophagy-related gene and protein expression in vivo and in vitro showed that the autophagy pathway was significantly activated in the high glucose/carbohydrate groups, while was inhibited after activation of FXR. Together, these results demonstrate that FXR regulates lipid metabolism disorders induced by high glucose through the FXR/FASN and FXR/SHP/SREBP-1c pathways, and alleviates ER stress and modulates autophagy.