Fenugreek Seeds Inhibit Hepatic VLDL Overproduction by Attenuating Metabolic Inflammatory Stress

Fenugreek (Trigonella foenum-gracecum L), an annual legume, has been well known for its medicinal properties in treating metabolic diseases. It is a new crop in Nebraska. Its seed contains a number of health-enhancing bioactive compounds, including diosgenin, galactomannan, and 4-hydroxyisoleucine. These compounds synergistically exert multiple health effects on anti-obesity and type 2 diabetes. In this study, we characterized the underlying molecular mechanisms of fenugreek seeds in anti-hyperlipidemia and anti-hyperglycemia. Using a genetic induced hyperlipidemia and a high fat diet (HFD) induced insulin resistance mouse models, we found that a diet rich in fenugreek seeds (2%) was able to lower hypertriglyceridemia induced by depletion of the cyclic AMP responsive element H (CREBH). This phenotype was accompanied by reduced levels of plasma apolipoprotein B100 (apoB) and inflammatory cytokine TNFα. Fenugreek seed feeding inhibited biosynthesis of apoB, and the assembly and secretion of very low density lipoprotein (VLDL) in the liver of CREBH-null mice. Fenugreek seed feeding also induced expression of mitochondrial fatty acid β-oxidation genes, such as PPARα and CPT-1α. Treatment with fenugreek seeds also attenuated ER stress and metabolic inflammation in CREBH-null hepatocytes, indicated by less expression of GRP78 protein, reduced phosphorylation of eIF2α and JNK. Furthermore, fenugreek seed feeding improved insulin sensitivity in a HFD induced insulin resistance mouse model as evidenced by the lower blood glucose levels in a glucose tolerance test and an insulin tolerance test compared to the paired fed-untreated control mice. Fenugreek seeds exerted anti-diabetic effect by enhancing glucose uptake in adipose tissue and liver. Taken together, our study provided new mechanistic insight into the triacylglycerol lowering properties and anti-diabetic nature of fenugreek seeds. This suggests therapeutic potential of fenugreek seed against metabolic disorders and may increase value of Nebraska-grown fenugreek.