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  • In cholesterol synthesis HMG CoA

    2020-10-12

    In cholesterol synthesis, HMG-CoA reductase is the rate limiting step in cholesterol biosynthesis. Statins or HMG-CoA reductase inhibitors are commonly used for management of hypercholesterolemia. The presence of an HMG-like moiety on these drugs allows them to competitively bind to the catalytic domain of the target enzyme, which results in an observed inhibitory effect as shown in HMG-CoA reductase. In order to assess the effect of SN extract on cholesterol synthesis inhibition we examined the effect of SNF on the activity of HMG-CoA reductase. SN extract and pravastatin showed a significant reduction in HMGR activity. The inhibition effect was observed to be increased in response to increasing HMG-CoA concentration and progressively reached its maximum activity or saturation. It can be noted that SN extract may have caused a direct binding to the catalytic domain of HMGR. Islam and colleges reported that dietary polyphenols can reduce cholesterol biosynthesis by binding to HMGR and blocking the binding of nicotinamide phenethyl dinucleotide phosphate. Curcumin binds to the HMG-CoA site on the enzyme similar to the statins. Epigallocatechin gallate potently inhibits HMGR activity by competitively binding to the cofactor site of the reductase. Peng and coworkers suggested that polyphenols-rich mulberry water extracts have hypolipidemic properties via inhibiting lipid synthesis (decreased the expression of HMGR) and promoting lipid degradation. It can be inferred that SN extract containing polyphenols may contribute to inhibiting HMGR activity.
    Conflicts of interest
    Acknowledgments
    Introduction Elevated serum cholesterol levels have been shown to be an independent risk factor for coronary heart disease (Castelli, 1984). The introduction of statins in the 1980s was a revolution in the treatment of hypercholesterolemia (Endo, 2008). Absolute risk reduction depends on serum cholesterol levels prior to treatment, the untreated cardiovascular disease risk, the magnitude of cholesterol reduction and the time point for the start of treatment. Large-scale primary and secondary prevention trials with statins have demonstrated a marked reduction in cardiovascular morbidity and mortality (Shepherd et al., 1995). One mmol/L (38.7 mg/dl) reduction inserum cholesterol reduces cardiovascular risk by 22% (Baigent et al., 2005). Nonetheless, meta-analysis of the statin trials point at a considerable residual cardiovascular risk in statin-treated patients (Heart Protection Study Collaborative, 2002). Inadequate cholesterol-lowering in patients on statins clearly contributes to this residual cardiovascular disease risk (Boekholdt et al., 2014). Cholesterol is provided either by the diet (about 20%) or by endogenous synthesis in potentially all cells of the body (about 80%) (Cohen, 2008; Wang, 2007) (Fig. 1). Both endogenous cholesterol synthesis and intestinal cholesterol absorption regulate total serum cholesterol levels (Weingärtner, Lütjohann, Böhm, & Laufs, 2010). Humans with high cholesterol synthesis exhibit adequate low-density lipoprotein-cholesterol (LDL-C) reduction on statins, whereas those with high cholesterol absorption are characterized by suboptimal LDL-C reduction (Farnier et al., 2009; Gylling & Miettinen, 2002; Teoh et al., 2009; Thuluva et al., 2005). Notably, the inhibition of cholesterol synthesis increases both cholesterol and phytosterol absorption (van Himbergen et al., 2009). Phytosterols are structural homoloogues to cholesterol, which are of plant and dietary origin. The main representatives are campesterol and sitosterol and their blood levels reflect cholesterol absorption rates.
    The concept of individualized cholesterol-lowering therapy Early results from the landmark statin trial “4S” demonstrated, that patients with high baseline cholesterol absorption did not benefit from statin treatment (Miettinen, Gylling, Strandberg, & Sarna, 1998). On the contrary, patients with high cholesterol absorption were characterized by a 16.6% increase in cardiovascular events on statin monotherapy (Fig. 2). Miettinen and colleagues concluded, that patients with high baseline cholesterol synthesis are responders to statin therapy whereas, on the other hand, patients with high cholesterol absorption are non- or “adverse”-responders. Results of cholesterol-lowering trials throughout the last three decades reaffirm the early findings by Miettinen et al. (1998) that roughly a quarter of patients on statin monotherapy do not benefit from statin monotherapy, but need an additional cholesterol absorption inhibitor. These findings inevitably lead to the idea of “individualizing cholesterol-lowering therapy” guided by differences in cholesterol metabolism (Miettinen et al., 1998; Weingärtner, Lütjohann, Böhm, & Laufs, 2011). This emerging concept is further supported by results from recently published genetic association studies. In line with this evidence, proxies of cholesterol absorption and synthesis and a strategy with a detailed genetic analysis of cholesterol homeostasis-regulating genes might be required to optimize cholesterol-lowering therapy.