Dyslipidemia is a metabolic condition characterized by abnormal plasma lipid or lipoprotein levels. Persistently elevated LDL-C, triglyceride-rich lipoproteins and their remnants, and lipoprotein(a) [Lp(a)] can all promote atherosclerotic cardiovascular disease. In addition to traditional lipid-lowering pathways, PCSK9, LPA, APOC3, and ANGPTL3 have become important targets for precision lipid intervention.

Keywords: dyslipidemia; low-density lipoprotein cholesterol; PCSK9; lipoprotein(a); APOC3; ANGPTL3; lipoprotein lipase; atherosclerosis; antisense oligonucleotide; siRNA

1 Metabolic Basis of Dyslipidemia and Cardiovascular Risk

1.1 Major Types of Dyslipidemia

Dyslipidemia may present as elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), or triglycerides, as well as reduced high-density lipoprotein cholesterol or abnormally elevated lipoprotein(a) [Lp(a)]. Elevated LDL-C mainly reflects an increased cholesterol burden carried by apolipoprotein B-containing lipoprotein particles. Elevated triglycerides are commonly accompanied by accumulation of triglyceride-rich lipoproteins and their remnants, whereas Lp(a) is an independent lipoprotein risk factor strongly influenced by genetic determinants.

1.2 LDL and Atherosclerosis

LDL particles contain apolipoprotein B100 (apoB100) as their principal structural protein. When circulating apoB-containing lipoprotein particles remain elevated over time, they can enter and become retained within the arterial intima, where they undergo oxidation, aggregation, or other modifications. Modified lipoproteins are taken up by macrophages and promote foam-cell formation, followed by inflammatory-cell recruitment, smooth muscle-cell migration, and extracellular matrix remodeling, ultimately driving atherosclerotic plaque formation.

1.3 Risks Associated With Triglyceride-Rich Lipoproteins and Their Remnants

Chylomicrons and very-low-density lipoproteins (VLDL) are hydrolyzed by lipoprotein lipase (LPL), generating cholesterol-rich remnant particles. Some remnants can enter the arterial wall and promote lipid accumulation and inflammation. Therefore, elevated triglycerides not only reflect metabolic dysfunction but may also indicate an increased burden of atherogenic remnant particles. APOC3, ANGPTL3, ANGPTL4, and ANGPTL8 can all influence this process by regulating LPL activity or remnant clearance.

1.4 Lp(a)-Associated Risk

Lp(a) consists of an LDL-like particle containing apoB100 covalently linked through a disulfide bond to apolipoprotein(a) [apo(a)]. Lp(a) can be retained within the arterial intima and transport oxidized phospholipids, thereby promoting endothelial dysfunction, inflammation, lipid deposition, and vascular calcification. Plasma Lp(a) levels are primarily determined by the LPA gene and apo(a) isoform size and are generally not substantially altered by routine dietary or exercise interventions.

2 Traditional Lipid-Lowering Targets and Therapeutic Limitations

2.1 HMG-CoA Reductase

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR), reducing cholesterol synthesis in hepatocytes and increasing low-density lipoprotein receptor (LDLR) expression through feedback regulation. This enhances clearance of circulating LDL particles. Lovastatin, Simvastatin, Atorvastatin, Rosuvastatin, and related compounds are representative agents for studying cholesterol synthesis and LDLR regulation.

2.2 Cholesterol Absorption and Bile Acid Cycling

Ezetimibe inhibits NPC1L1-mediated intestinal cholesterol absorption, reducing cholesterol delivery to the liver and promoting LDLR upregulation. Bile acid sequestrants reduce bile acid reabsorption, forcing the liver to consume cholesterol to synthesize new bile acids. Both strategies enhance hepatic clearance of circulating LDL, but they act at different stages involving intestinal cholesterol absorption and enterohepatic bile acid circulation.

2.3 PPARα and Triglyceride Metabolism

Fibrates such as Fenofibrate and Gemfibrozil primarily activate peroxisome proliferator-activated receptor α (PPARα), promote fatty acid oxidation, enhance the metabolism of triglyceride-rich lipoproteins, and may reduce APOC3 expression. These agents are mainly used in triglyceride-metabolism research, and their effects on LDL-C and HDL-C depend on baseline lipid levels and lipoprotein composition.

2.4 Other Traditional Metabolic Targets

Bempedoic acid inhibits ATP citrate lyase and reduces substrate availability for cholesterol synthesis. Lomitapide inhibits microsomal triglyceride transfer protein and reduces VLDL and apoB-lipoprotein assembly. Mipomersen suppresses APOB expression and reduces apoB100 synthesis. Nicotinic acid affects adipose-tissue lipolysis and hepatic VLDL production. These strategies target different stages of cholesterol synthesis, lipoprotein assembly, and fatty acid supply.

2.5 Residual Cardiovascular Risk

Even when LDL-C is effectively controlled, some patients may retain risk associated with triglyceride-rich lipoprotein remnants, Lp(a), metabolic inflammation, and other apoB-containing particles. Lipid-intervention research has therefore expanded from the exclusive reduction of LDL-C to multitarget strategies that also evaluate apoB, non-HDL-C, remnant cholesterol, triglycerides, and Lp(a).

Table 1 Major Intervention Targets in Dyslipidemia

3 The PCSK9-LDLR Axis and LDL-C Regulation

3.1 LDLR-Mediated LDL Clearance

LDLR on the hepatocyte surface recognizes apoB100 and binds circulating LDL particles, which are then internalized through receptor-mediated endocytosis. Under normal conditions, the acidic endosomal environment promotes dissociation of LDL from LDLR. LDL particles are transported to lysosomes for degradation, whereas LDLR recycles back to the plasma membrane to continue clearing LDL. The efficiency of LDLR recycling directly influences the liver’s capacity to remove circulating LDL particles.

3.2 PCSK9 Promotes LDLR Degradation

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized and secreted by hepatocytes. After PCSK9 binds the extracellular domain of LDLR, it prevents normal dissociation and recycling of LDLR within the endosome, directing the PCSK9-LDLR complex toward lysosomal degradation. This reduces the number of LDLRs on the hepatocyte surface and decreases clearance of circulating LDL particles.

3.3 PCSK9 Monoclonal Antibodies

Monoclonal antibodies such as Alirocumab, Evolocumab, and Tafolecimab bind circulating PCSK9, block its interaction with LDLR, reduce LDLR degradation, and increase hepatic uptake of LDL particles. This strategy directly targets extracellular PCSK9 and is suitable for studies of PCSK9 neutralization, LDLR stability, and LDL uptake.

3.4 PCSK9-Targeted Nucleic Acid Drugs

Inclisiran uses hepatocyte-targeted siRNA delivery to reduce PCSK9 mRNA and suppress PCSK9 production at the level of protein synthesis. Antisense oligonucleotides such as SPC5001 can similarly bind PCSK9 mRNA and inhibit its expression. The major difference between nucleic acid drugs and monoclonal antibodies is that the former act on intracellular hepatic mRNA, whereas the latter neutralize circulating PCSK9 protein.

4 Structure, Pathogenic Effects, and Intervention Strategies of Lp(a)

4.1 Molecular Composition of Lp(a)

The core of Lp(a) is an LDL-like particle containing apoB100, to which apo(a) is attached through a disulfide bond. Apo(a) is encoded by the LPA gene and contains multiple Kringle domains structurally similar to those of plasminogen. Apo(a) isoform size varies substantially among individuals and can affect the efficiency of Lp(a) synthesis and its plasma concentration.

4.2 Vascular Injury Caused by Lp(a)

Lp(a) can enter and become retained within the arterial intima, promoting cholesterol deposition and foam-cell formation. Oxidized phospholipids carried by Lp(a) can activate endothelial and immune cells, increase chemokine expression, recruit monocytes, and promote vascular inflammation and calcification. Because apo(a) shares partial structural similarity with plasminogen, Lp(a) may also influence fibrinolysis and thrombosis-related processes.

4.3 Nucleic Acid Drugs Targeting LPA Expression

Pelacarsen is an antisense oligonucleotide targeting LPA mRNA, whereas Olpasiran uses siRNA to reduce hepatic apo(a) synthesis. Both drug classes reduce Lp(a) particle formation at the protein-synthesis stage, but they differ in nucleic acid structure, delivery system, intracellular mechanism, and duration of pharmacological effect.

4.4 Inhibition of Lp(a) Particle Assembly

Small molecules such as Muvalaplin interfere with the interaction between apo(a) and apoB100 and thereby inhibit assembly of mature Lp(a) particles. This strategy does not directly alter LPA gene expression but instead acts at the lipoprotein-particle assembly stage, providing a mechanistic tool distinct from nucleic acid-based therapies.

4.5 Lp(a) Measurement and Data Interpretation

Lp(a) may be reported as mass concentration or particle concentration. Because apo(a) isoform size varies, mg/dL and nmol/L cannot be converted using a universal fixed factor. When evaluating compounds targeting Lp(a), the analytical platform and measurement units should remain consistent, and changes in Lp(a) particle number should be distinguished from changes in particle cholesterol content.

5 APOC3 and Triglyceride-Rich Lipoprotein Metabolism

5.1 Lipoprotein Distribution of APOC3

Apolipoprotein C3 (APOC3) is primarily synthesized in the liver and is distributed among chylomicrons, VLDL, HDL, and a small proportion of LDL particles. Elevated plasma APOC3 is commonly associated with accumulation of triglycerides and triglyceride-rich lipoprotein remnants and is an important target in research on severe hypertriglyceridemia and remnant metabolism.

5.2 Regulation of Lipolysis by APOC3

LPL is located on the capillary endothelial surface and hydrolyzes triglycerides within chylomicrons and VLDL, releasing fatty acids for use or storage by muscle and adipose tissue. APOC3 inhibits LPL-mediated lipolysis, prolonging the residence time of triglyceride-rich lipoproteins in the circulation and increasing the triglyceride burden.

5.3 Effects of APOC3 on Remnant Clearance

In addition to inhibiting LPL-mediated lipolysis, APOC3 can delay hepatic uptake of triglyceride-rich lipoprotein remnants. This involves LDLR, low-density lipoprotein receptor-related protein 1 (LRP1), and other hepatic clearance pathways. Consequently, APOC3 inhibition can promote both lipolysis and remnant clearance.

Volanesorsen and Olezarsen are antisense oligonucleotides targeting APOC3 mRNA, whereas Plozasiran and related agents use siRNA to reduce hepatic APOC3 synthesis. Target intervention can be evaluated by measuring APOC3 protein, LPL activity, triglycerides, remnant cholesterol, and chylomicron changes, together with hematological and hepatic safety indicators.

6 ANGPTL3 and the Lipoprotein Lipase Inhibitory Network

6.1 ANGPTL3 Expression and Function

Angiopoietin-like protein 3 (ANGPTL3) is mainly synthesized and secreted by the liver and inhibits LPL and endothelial lipase. After forming a functional complex with ANGPTL8, ANGPTL3 potently inhibits LPL in a tissue- and nutritional-state-dependent manner. In the fed state, circulating ANGPTL3–ANGPTL8 mainly suppresses LPL in oxidative tissues such as the heart and skeletal muscle, whereas adipose-tissue LPL is additionally regulated by the local ANGPTL4–ANGPTL8 axis, thereby directing triglyceride-derived fatty acids toward adipose storage.

Figure 1 Mechanism of ANGPTL3-mediated regulation of lipoprotein lipase activity and triglyceride metabolism

6.2 Functional Differences Between ANGPTL4 and ANGPTL8

ANGPTL4 is expressed in adipose tissue, skeletal muscle, liver, heart, intestine, macrophages, and other tissues and mainly regulates LPL during fasting and local fatty acid partitioning. ANGPTL8 primarily cooperates with ANGPTL3 and is regulated by feeding and nutritional status. Because ANGPTL4 has broad tissue functions, systemic inhibition may disturb local lipid partitioning. Lipid-lowering drug research therefore focuses more heavily on liver-derived ANGPTL3.

6.3 ANGPTL3 and LDL Metabolism

ANGPTL3 inhibition lowers not only triglycerides but also LDL-C. This effect is not entirely dependent on LDLR and may involve changes in VLDL production, lipoprotein lipolysis, remnant processing, and LDL formation. ANGPTL3 is therefore suitable for studying lipoprotein regulation under conditions of limited LDLR function.

6.4 ANGPTL3-Targeted Drugs

Evinacumab is a monoclonal antibody targeting ANGPTL3 and blocks the inhibitory effect of circulating ANGPTL3 on lipases. Vupanorsen is an antisense oligonucleotide targeting ANGPTL3 mRNA, whereas ARO-ANG3 (Zodasiran) uses siRNA to reduce hepatic ANGPTL3 synthesis. These approaches act either on circulating protein or intracellular hepatic mRNA.

7 Comparison and Experimental Evaluation of Emerging Lipid Targets

7.1 Metabolic Positioning of Different Targets

PCSK9 primarily regulates LDLR abundance and LDL-particle clearance and is generally evaluated using LDL-C and apoB reduction. LPA-targeting strategies act on apo(a) synthesis or Lp(a) particle assembly. APOC3 and ANGPTL3 more directly influence lipolysis and remnant processing of triglyceride-rich lipoproteins, whereas ANGPTL3 additionally affects LDL and HDL metabolism.

Table 2 Comparison of PCSK9, LPA, APOC3, and ANGPTL3

7.2 In Vitro Research Models

PCSK9 studies can use hepatocytes to measure PCSK9 expression and secretion, LDLR protein levels, and uptake of fluorescently labeled LDL. APOC3 and ANGPTL3 studies can combine hepatocyte expression models, LPL enzymatic assays, and triglyceride-rich lipoprotein hydrolysis assays. Lp(a) research requires particle-assembly systems capable of expressing both apo(a) and apoB100. Because ordinary rodents lack an Lp(a) metabolic system fully corresponding to that of humans, model selection and extrapolation require particular caution.

7.3 Animal and Preclinical Evaluation

Lipid-targeted drug studies should measure total cholesterol, LDL-C, HDL-C, triglycerides, non-HDL-C, apoB, APOC3, ANGPTL3, and Lp(a), together with hepatic lipid metabolism, lipoprotein-particle distribution, and atherosclerotic plaque burden. Nucleic acid drugs should additionally be evaluated for hepatic target-gene silencing efficiency, off-target effects, innate immune activation, and long-term tissue safety.

7.4 Boundaries of Data Interpretation

An increase in HDL-C does not necessarily indicate enhanced cardiovascular protection, and triglyceride reduction cannot fully replace measurement of apoB particles and remnant cholesterol. LDL-C, apoB, non-HDL-C, triglycerides, and Lp(a) reflect different lipoprotein characteristics. Research endpoints should therefore be selected according to target mechanism rather than using a single lipid indicator to summarize the entire pharmacological effect.

8 Lipid-Metabolism Targets, Lipid-Lowering Drugs, and Research Compounds

PCSK9, LPA, APOC3, and ANGPTL3 correspond respectively to LDLR recycling, Lp(a) formation, triglyceride-rich lipoprotein processing, and the lipase-inhibitory network. Combining traditional lipid-lowering compounds with emerging targeted therapeutics enables more systematic evaluation of cholesterol synthesis, lipoprotein assembly, particle clearance, and residual lipid-related cardiovascular risk.

References

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[2] Tall AR, et al. Addressing Dyslipidemic Risk Beyond LDL-Cholesterol. J Clin Invest. 2022;132(1).

[3] O'Donoghue ML, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022;387(20):1855–1864.

[4] Nicholls SJ, et al. Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial. JAMA. 2023;330(11):1042–1053.

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[3] Methods for Establishing Animal Models of Cardiovascular Diseases