Phytoceuticals in Fenugreek Ameliorate VLDL Overproduction and Insulin Resistance via the Insig Signaling Pathway

Scope This study aims to characterize the effect of fenugreek ( Trigonella foenum‐graecum ) seed and its phytoceutical trigonelline in antimetabolic inflammation and ameliorating overproduction of very low density lipoprotein (VLDL) in insulin resistance. Methods and Results Two groups of genetic hyperlipidemic mice generated by depletion of cAMP responsive element binding protein H (CREBH) are fed either a chow containing 2% fenugreek seed or vehicle for 7 weeks. Q‐RT‐PCR and immunoblotting analysis demonstrated that fenugreek seed containing diet inhibits hepatic SREBP‐1c activation and the subsequent de novo lipogenesis by enhancing expression of insulin‐inducible gene‐1 (Insig‐1) and gene‐2 (Insig‐2). mRNA expression of PPARα and its target genes that are involved in fatty acid β‐oxidation are also upregulated in the fenugreek seed fed‐mice which is accompanied by significantly reduced hepatic lipid accumulation and VLDL secretion, improved endoplasmic reticulum (ER) stress, and ameliorated metabolic inflammation. These actions enhance insulin sensitivity and improve hyperlipidemia. In vitro, treating a rat hepatoma cell line, McA‐RH7777 (McA), with trigonelline is able to recapitulate the results observed in vivo. Conclusions This study unveils a novel mechanism of fenugreek seed and trigonelline in countering hepatic VLDL overproduction and insulin resistance by enhancing the Insig signaling pathways and ameliorating metabolic inflammatory stress in the liver.