A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD

Figures

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  Figure 1. LDLR-dependent and -independent pathways to manage circulating LDL levels. De novo lipogenesis (DNL) provides fatty acids and cholesterol for the assembly of apoB-containing very low-density lipoproteins (VLDL), where apoB serves as the main protein and microsomal triglyceride transfer protein (MTP) facilitates the assembly of VLDL. By inhibiting DNL by Nexletol (ACLY inhibitor), it is possible to reduce the synthesis and secretion of VLDL. Inhibition of MTP by lomitapide and silencing of apoB production by mipomersen also restricts VLDL secretion and leads to reduced levels of LDL. Dietary cholesterol absorption by bile acid (BA) sequesters and ezetimibe, an NPC1L1 inhibitor, also reduces circulating LDL. Other pathways to reduce LDL are to inhibit the degradation of LDLR by PCSK9 and enhance clearance of LDL. Inclisiran (PCSK9 ASO) and evolocumab (PCSK9 mAb) enhance LDL clearance. LDL and triglyceride-rich lipoproteins can also be removed by silencing apoCIII and ANGPTL3 by using volanesorsen (apoCIII ASO), vupanorsen (ANGPTL3 ASO), and evinacumab (ANGPTL3 mAb). DNL, de novo lipogenesis; BA, bile acid; TRL, triglyceride-rich lipoproteins; LPL, lipoprotein lipase; FA, fatty…

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  Figure 2. LDLR modulates circulating levels of LDL and lowers the risk of ASCVD. Panel (A): LDLR loss-of-activity mutation in humans is associated with elevated LDL, resulting in familial hypercholesterolemia (HoFH and HeFH) and an increase in the risk of ASCVD. Panel (B): PCSK9 and IDOL also regulate LDLR activity via degradation of the LDLR protein. Inhibition of PCSK9 and IDOL by mAb increases LDL activity and decreases circulating LDL. Panel (C): Gain of LDLR activity as a result of splice site variants and deletion of 3′ UTR lowers circulating LDL. The 2.5 kb LDLR 3′UTR sequences contain binding sites of miRNAs [89,90,91,92,93] known to repress LDLR expression.

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  Figure 3. LDLR-independent pathways regulate circulating LDL. (A): Liver synthesizes and secretes VLDL lipoproteins in the circulation. Intrahepatic assembly of VLDL requires apoB, MTP and triglycerides. ApoC-III is a component of VLDL and chylomicron remnants, and also an inhibitor of lipoprotein lipase. Another protein, ANGPTL3, also facilitates secretion of TRL from the liver and impairs clearance of TRL. Thus, apoB, apoC-III and ANGPTL3 increase the pro-atherogenic lipoproteins. (B): Hepatic VLDL secretion can be lowered by the reduced production of apoB. In FHBL individuals, the nonsense mutation in the apoB gene results in low levels of apoB, resulting in less secretion of VLDL. ApoC-III and ANGPTL3 antisense therapies both influence hepatic secretion of TRL and increase LPL activity, leading to reductions in apoB-containing lipoproteins and TG. Green color arrows indicate production of lipoproteins and blue color arrows indicate clearance of lipoproteins.

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  Figure 4. LDLR gain-of-function mutation [194]. (A): The LDLR gene has two polyadenylation sites. The 2.5 kb DNA segment flanks the distal site. (B): Normally, polyadenylation occurs at the distal site, and as a result, the binding sites for repressors of the LDLR gene remain intact. (C): When the 2.5 kb 3′UTR region is missing, polyadenylation occurs at the proximal site. This results in the upregulation of LDLR gene expression by 2-fold and a circulating LDL reduction of 74% in carriers compared to non-carriers of the mutation.

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  Figure 5. CRISPR-mediated gene/base editing to lower LDL in hypercholesterolemic patients. (A): CRISPR/Cas9-mediated excision of the 2.5 kb 3′UTR region of LDLR in FH patient-derived cells and in mice increases LDLR activity and mRNA [211]. (B): Base editing of ANGPTL3 resulting in the loss of function decreases LDL by enhanced clearance as a result of LPL activation. Inactivation of ANGPTL3-mediated lowering of LDL occurs via an LDLR-independent pathway. Green shows protection from CVD. Red arrow indicates increase in CVD risk.