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  • br ACL Inhibition Lowering Blood LDL C to Reduce

    2023-09-18


    ACL Inhibition: Lowering Blood LDL-C to Reduce ASCVD Risk Given its strategic position in the lipid biosynthesis pathway, ACL has been considered an attractive target for lipid-lowering even before statins and their effects on cholesterol homeostasis were elucidated (Box 2). Cells carefully maintain intracellular free cholesterol concentrations within a narrow range, primarily through a highly sensitive regulatory feedback mechanism involving the transcription factor, SREBP-2 (Figure 1, Figure 3; reviewed in [27]). Indeed, statins exploit this pathway by inhibiting liver HMG-CoA reductase, thereby reducing intracellular cholesterol levels and triggering SREBP-2-mediated LDL receptor (LDLR) upregulation in human hepatocytes 10, 11, 22, 27. This can result in a new homeostatic state where cells acquire more cholesterol from circulating LDL particles, thus reducing LDL-C [10] and its potential to cause ASCVD (Figure 3) [1]. Given the dependence of cholesterol biosynthesis on ACL activity, ACL inhibition is anticipated to promote effects on LDLR-mediated LDL particle clearance in a manner similar to statins [51]. This is supported by in vitro studies in human liver cells demonstrating that LDLR upregulation can result from ACL suppression via both siRNA-mediated and pharmacological ACL suppression using (–)-hydroxycitrate 51, 52. Other approved LDL-C-lowering therapies can also impact LDL metabolism (in a manner similar to statins) by mimicking dietary cholesterol restriction via reducing cholesterol LDC000067 (Figure 3). A meta-regression analysis of 49 clinical cardiovascular outcome trials showed that oral therapeutic statin administration, or non-statin therapies such as Niemann-Pick C1-Like 1 (NPC1L1) inhibition by ezetimibe and bile acid sequestrants that mimic some aspect of the SREBP-2 cholesterol-sensing mechanism, provided an approximately 23% relative risk reduction of major vascular events, as defined by a composite of acute myocardial infarction or other acute coronary syndrome, cardiovascular death, stroke, or coronary revascularization, per 1mmol/L of plasma LDL-C lowering [2]. Moreover, lowering plasma LDL-C levels by increasing LDLR activity via injectable anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody therapy was recently shown to also reduce the number of major vascular events in a cardiovascular disease outcomes trial, suggesting that preserving LDLR activity may be mechanistically sufficient to lower plasma LDL-C and associated cardiovascular disease risk [53]. These findings have led to the consensus that lowering LDL-C via LDLR-mediated clearance can provide a proportional and predictable reduction in major vascular events [1]. Therefore, ACL inhibition might be expected to produce biologically equivalent effects on LDL metabolism and ASCVD risk reduction, as observed with other interventions such as statins, PCSK9 inhibition, and ezetimibe, which also upregulate LDLR activity (Figure 3). In the absence of clinical efficacy endpoints, investigators and drug developers have turned to the principles of Mendelian randomization as a means to inform cardiovascular risk/benefit associated with novel drug targets [54]. This approach has been validated retrospectively in humans for ASCVD using LDL-C lowering variants in HMGR, and prospectively, to predict the outcomes of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)55, 56 and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trials using HMGR/NPC1L1 (target of Vytorin, simvastatin/ezetimibe combination) and PCSK9 variants, respectively 2, 55. Using similar methods, a study reported the effects of lowering LDL-C blood levels, as being mediated by multiple independently inherited single-nucleotide polymorphisms (SNPs) in the gene region encoding ACL (gene: ACLY) [57]. In addition to lowering LDL-C, these variants were also associated with a shift in plasma biomarkers such as Apolipoprotein B (ApoB), high-density lipoprotein-C (HDL-C), high-sensitivity C-reactive protein (hsCRP), and triglycerides in a way that was remarkably similar to LDL-C-lowering polymorphisms in HMGR and the effects of statins in randomized clinical trials [57]. These findings strongly suggest that the mechanism of LDL-C lowering via ACL inhibition might be biologically equivalent to that of statins. However, this remains to be fully demonstrated. Importantly, by constructing a genetic score based on the weighted association of these SNPs with lower LDL-C levels, these studies have also shown that exposure to lifelong lower LDL-C levels mediated by SNPs in ACLY was causally associated with a reduction in ASCVD risk; furthermore, when the odds ratios were adjusted per 10mg/dL LDL-C lowering, the relative risk reduction appeared to be similar to that observed with lower plasma LDL-C mediated by SNPs in other validated genes including HMGR, NPC1L1, PCSK9, and LDLR[57]. Using a 2×2 factorial analysis designed to mimic the effects of combination therapy in a randomized clinical trial, subjects were first randomized based on their ACLY LDL-C score, then, by either their HMGR LDL-C score or NPC1L1 LDL-C score [57]. These analyses showed that ACLY SNPs provided additive LDL-C lowering and a proportional reduction in ASCVD risk, when combined with either HMGR or NPC1L1 SNPs [57]. This suggests that ACL inhibitors might be able to provide an additive ASCVD benefit when combined with existing LDL-C-lowering therapies such as statins and ezetimibe in patients with hypercholesterolemia. However, further studies are needed, and whether pharmacological inhibition of ACL will corroborate these findings remains to be established.