Chenodeoxycholic acid (CDCA) alleviates high fat diet-induced lipid deposition via FXR/SHP/PIAS1/SUMO1-dependent SREBP1K264 SUMOylation in yellow catfish.

Abstract

Background: High-fat diet (HFD) induced intestinal lipid accumulation and impaired intestinal health. Chenodeoxycholic acid (CDCA) have a positive effect on attenuating lipid accumulation, but its mechanism in HFD-induced lipid metabolism disorders and intestinal health remained unclear.

Objectives: The study explored the mechanism of dietary CDCA alleviating lipid deposition and metabolic changes induced by HFD.

Methods: Yellow catfish were fed diets containing control (10.58% lipid, CON), HFD (15.96% lipid), control supplemented with 0.90 g/kg CDCA (CDCA), and HFD supplemented with 0.90 g/kg CDCA (HFD+CDCA) for 10 weeks. Intestinal epithelial cells (IECs) were incubated 24 h in 0.5 mM fatty acid (FA) or 50 μM CDCA after 4 h with or without farnesoid X receptor (fxr), small ubiquitin-related modifier 1 (sumo1) or protein inhibitor of activated signal transducer and activators of transcription 1 (pias1)-siRNA. Triglyceride, quantitative polymerase chain reaction, immunoblotting, electrophoretic mobility shift assay and chromatin immunoprecipitation were performed in intestine and IECs. SUMOylation of sterol regulatory element binding protein 1 (SREBP1) was investigated in IECs and HEK293T cells.

Results: Dietary CDCA ameliorated HFD-induced increase of triglyceride concentrations, lipogenesis and FA uptake, and reduction of lipolysis and lipid transport, bile acid absorption and transport, and SUMOylation. FXR activated SUMO1 transcription, which promoted SUMOylation of SREBP1 and inhibited SREBP1 nuclear translocation and accordingly helped CDCA alleviate FA-induced lipid accumulation. Lysine 264 was the important SUMOylation site of SREBP1 by SUMO1, whose SUMOylation reduced binding ability to FA synthase (FAS), acetyl-CoA carboxylase α (ACCα) and stearoyl-CoA desaturase 1 (SCD1) promoters. Activation of FXR enhanced interaction between short heterodimeric partners (SHP) and PIAS1, which promoted SUMO1 attachment to SREBP1, inhibited transcription of fas, accα and scd1.

Conclusions: CDCA alleviated HFD-induced lipid accumulation by promoting SUMOylation of SREBP1 at lysine 264 via FXR/SHP/PIAS1/SUMO1 pathway, providing innovative mechanisms for CDCA alleviating HFD-induced lipid accumulation in vertebrates.