Diallyl trisulfide attenuates metabolic syndrome via integrated modulation of PCSK-9/LDL-R axis, redox homeostasis, and inflammatory cytokine networks in high-carbohydrate high-fat (HCHF) diet-fed rats

Background Metabolic syndrome (MetS), a cluster of biochemical and physiological alterations leading to the development of cardiovascular disease and type 2 diabetes (T2DM), is a major health concern worldwide. Recently, elevated level of proprotein subtilisin/kexin type-9 (PCSK-9) along with dyslipidemia, high blood pressure, blood sugar, and triglycerides have been linked to the establishment and advancement of Mets. Aim of this study In this study, we explored the protective effects of diallyl trisulfide (DATS), a natural organosulfur compound derived from garlic, in a high-carbohydrate high-fat (HCHF) diet-induced rat model of MetS. Results Herein, we report that DATS improves MetS parameters via significantly downregulating the mRNA expression of PCSK-9 (1.59-fold when compared with HCHF control) and its transcriptional activator, HNF-1α. Similarly, the mRNA expression (−3.19-fold) and the ex-vivo enzymatic activity of 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase (HMG-R) were attenuated in DATS-treated rats. In contrast, DATS significantly increased the low-density lipoprotein-receptor (LDL-R) mRNA expression by 1.98-fold. This unique regulation of PCSK-9/LDL-R axis, HNF1α, and HMG-R was well corroborated by the reduced plasma level of PCSK-9, low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs). Furthermore, the mRNA expression and circulatory level of inflammatory cytokines i.e ., interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α) and chemokines i.e ., Chemokine (C-X-C motif) ligand (CXCL)-1, CXCL-2, and monocyte chemoattractant protein-1 (MCP-1) were also ameliorated after DATS intervention. The expression of peroxisome proliferator-activated receptors (PPAR)-α, β, and γ was also upregulated after treatment with DATS, when compared to untreated HCHF group. Conclusion This comprehensive investigation demonstrates that DATS mitigates HCHF diet-induced MetS by targeting molecular regulators of cholesterol homeostasis, oxidative stress, glycemic indices, and inflammation. These findings suggest that DATS may serve as a promising therapeutic agent in preventing and managing MetS and associated cardiometabolic risks.