High carbohydrate ingestion induces lipid accumulation through enhancing SCAP O-GlcNAcylation to activate SREBP1 in fish

Abstract

Fish are prone to lipid deposition when fed a high carbohydrate diet (HCD), making them suitable models for investigating the potential mechanisms of HCD-induced fat accumulation. In the present study, Nile tilapia and zebrafish liver cell lines (ZFL) were used to investigate the potential mechanisms of high carbohydrate-induced fat deposition. Our results found that HCD induces hepatic lipid accumulation and insulin resistance in fish. HCD activates the hexosamine biosynthetic pathway (HBP), increasing UDP-GlcNAc levels and upregulating hepatic OGT expression and O-GlcNAcylation. Interestingly, supplementing with the O-GlcNAcylation substrate glucosamine and inhibiting O-GlcNAcase (OGA) both promote triglyceride accumulation in ZFL. In contrast, inhibiting O-GlcNAc transferase (OGT) can block the triglyceride accumulation induced by glucose. Our further study results indicate that high carbohydrate enhances the protein stability of sterol regulatory element-binding protein cleavage-activating protein (SCAP) by increasing its O-GlcNAcylation level. This, in turn, promotes the formation of the SCAP-sterol regulatory element-binding protein 1 (SREBP1) complex, as well as the cleavage and nuclear translocation of SREBP1. Consequently, these processes regulate lipid anabolism and induce hepatic lipid accumulation. This finding provides a plausible explanation for the sustained activation of SREBP1 in the context of insulin resistance induced by HCD.

Keywords

High carbohydrate / O-GlcNAcylation / SCAP / SREBP1 / Lipid accumulation

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