A New Modality in Dyslipidemia Treatment: Antisense Oligonucleotide Therapy

Figures

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  Fig. 1. Modulation of gene expression by ASOs. ASOs can modulate gene expression by two different mechanisms. First, ASOs bind and occupy the target mRNA without triggering RNA degradation (occupancy-only mediated): (A) splicing modulation by base pairing with sequence elements in pre-mRNA to inhibit or enhance the utilization of splicing sites; (B) translation modulation by base pairing with mRNA, either to inhibit or activate translation through binding to inhibitory elements; (C) microRNA modulation either by base pairing with microRNA to inhibit the function of the microRNA or by base pairing with microRNA-binding sites of a particular mRNA to eliminate the effect of a particular microRNA. Second, ASOs induce target mRNA degradation (enzymatic RNA degradation): (D) DNA-like ASOs that trigger complementary RNA cleavage by RNase H1. ASO, antisense oligonucleotide.

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  Fig. 2. The metabolism of TRLs and the role of apoCIII. Triglyceride-rich VLDL is released from the liver and converted to IDL by lipoprotein lipase (LPL). Chylomicrons are formed in the intestine and transformed into chylomicron remnants by LPL. ApoCIII regulates TRL metabolism by inhibiting the activity of LPL (LPL-dependent pathway) and by interfering with hepatic clearance of TRL remnants (LPL-independent pathway). TRL, triglyceride-rich lipoprotein; apoCIII, apolipoprotein CIII; VLDL, very low-density lipoprotein; IDL, intermediate-density lipoprotein; LPL, lipoprotein lipase; CETP, cholesteryl ester transfer protein.

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  Fig. 3. Structure of Lp(a). (A) Lp(a) consists of a LDL-like moiety covalently linked by a single disulfide bond to the glycoprotein apo(a). The LDL-like moiety contains a single molecule of apoB100, an outer shell of PLs and unesterified FC, and a neutral lipid core consisting of CEs (primarily) and TGs. OxPLs are predominantly covalently bonded to apo(a), but are also found covalently linked to apoB100 and free in the lipid moiety. (B) Apo(a) consists of 10 different domains homologous to plasminogen K4 (named KIV in apo[a]), a KV, and an inactive, protease-like domain. Lp(a), lipoprotein(a); LDL, low-density lipoprotein; apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; PL, phospholipid; FC, free cholesterol; CE, cholesteryl ester; TG, triglyceride; OxPL, oxidized phospholipid; K4, kringle 4; KV, kringle 5-like domain; T, tail domain.

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  Fig. 4. TG metabolism and the role of ANGPTL3. Dietary fat is transported through the blood as part of chylomicrons. TGs in the chylomicrons are hydrolyzed by LPL. The GPIHBP1 transports LPL from the cell surface to the capillary endothelium. ANGPTL3, produced in the liver and secreted into the circulation, inhibits LPL in peripheral tissues. The function of ANGPTL3 as an LPL inhibitor is dependent on ANGPTL8, which is also produced in the liver and forms a complex with ANGPTL3. TG, triglyceride; ANGPTL3, angiopoietin-like protein 3; ANGPTL8, angiopoietin-like protein 8; LPL, lipoprotein lipase; GPIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.