## 3 Effect of PS on Components of MetS
### Effect of PS on Dyslipidemia and Its Complications  
Dyslipidaemia has emerged as a global epidemic. According to the Global Burden of Disease, Injuries, and Risk Factors study, morbidity and mortality attributable to dyslipidaemia worldwide have increased by 26.9 and 28.0%, respectively, over the past few decades [115; 116; 117]. Dyslipidaemia is characterised by increased fasting and postprandial  
Figure 4: Protective effect of PS supplementation against hypertension: current knowledge and future area of investigation. List of abbreviations: PS, _Piper sarmentosum_; \(\uparrow\), increase; \(\downarrow\), decrease; ADMA, asymmetric dimethyl arginine; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; SBP, systolic blood pressure; DBP, diastolic blood pressure; MABP, mean arterial blood pressure; ET-1, endothelin 1; RAAS, renin-angiotensin-aldosterone system; Na\({}^{+}\), sodium ion; H\({}_{2}\)O, water. triglyceride-rich lipoproteins, decreased HDL, and increased small, dense low-density lipoprotein (LDL) particles [118; 119]. The pathogenesis of dyslipidemia has been linked to oxidative stress. During the attack of free radicals on membrane lipoproteins and polyunsaturated fatty acids, many oxygenated compounds, particularly aldehydes, such as MDA and conjugated dienes, are produced. Many studies have found that serum MDA levels are higher in hyperlipidemia subjects and decrease after antioxidant supplementation, with similar findings in animal models of hyperlipidemiaaemia [120; 121]. Inflammation is also gaining attention for its potential role in the pathogenesis of dyslipidaemia [122; 123], as people with dyslipidemia generally have higher levels of inflammatory biochemical markers than those without dyslipidaemia [123]. Some studies have reported the hypolipidaemic effect of PS. In rats with fructose-induced MetS, the methanolic leaf extract of PS (125 mg/kg/day for 4 weeks) reduced total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL), and increased high-density lipoproteins (HDL) [68]. [PERSON] et al. [124] also reported similar results in ovariectomy-induced obese rats treated with the aqueous leaf extract of PS (125 mg/kg/day for 5 months). The aqueous leaf extract of PS (500 mg/kg/day for 28 days) also reduced serum TC, TG, and LDL, but did not change the HDL levels [125]. Additionally, 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR) activity was reduced by PS (the methanolic leaf extract 125 mg/kg/day for 4 weeks) in fructose-induced MetS rats and ovariectomy-induced obese rats (the aqueous leaf extract, 125 mg/kg/day for 5 months). HMGCR is the rate-controlling enzyme of the mevalonate pathway and is responsible for cholesterol synthesis in the liver [126]. A decrease in HMGCR expression/activity indicates a decrease in cholesterol production [127; 128]. This suggests that the hypolipidaemic effect of PS is primarily driven by a decrease in HMGCR activity, similar to that of statins. Thus, it could be used as an alternative therapy for hyperlipidemiaemia [124]. Notably, the methanolic extract of PS (4 weeks) improves the lipid profile in animals faster than the aqueous extract (3-5 months), indicating a better efficacy. Given the potential effects of PS on HMGCR, it is interesting to examine the effects of statins and PS in combination on the mevalonate pathway. Prolonged statin use has been frequently associated with muscle associated symptoms [129]. Thus, the combination could reduce the dose of statins required to achieve hypocholesterolem effects, thus lowering the risk of side effects. However, this speculation awaits validation from future studies. Figure 5 summarises the current knowledge on the effect of PS supplementation on hyperlipidemia and the further investigation required in this area. Overall, PS supplementation attenuated the adverse effects associated with MetS.