The potential of ANGPTL8 antagonism to simultaneously reduce triglyceride and increase HDL-cholesterol plasma levels
Open accessAbstract
Elevated triglyceride (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) plasma levels are risk factors for atherosclerosis and cardiovascular disease. Therefore, a drug that simultaneously reduces TG and increases HDL-C plasma levels has the potential to prevent and treat these diseases. Angiopoietin-like 3 (ANGPTL3) regulates plasma TG and HDL-C levels by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL), respectively. ANGPTL3 inhibition of LPL requires complex formation with ANGPTL8, which is not required for its inhibition of EL. Therefore, the entire pool of plasma ANGPTL3 can be classified as ANGPTL8-associated ANGPTL3 and ANGPTL8-free ANGPTL3, where the former inhibits LPL and the latter inhibits EL. ANGPTL8 antibodies or inhibitors that block its interactions with ANGPTL3 can disrupt or preclude the ANGPTL3-8 complex formation, resulting in fewer ANGPTL3-8 complexes (reduced LPL inhibition), but more free ANGPTL3 (enhanced EL inhibition). Therefore, ANGPTL8 antagonism increases LPL activity while decreasing EL activity, thus leading to reduced plasma TG while simultaneously increasing HDL-C levels. In humans, carriers of ANGPTL8 truncating variants consistently have lower TG but higher HDL-C levels, supporting this hypothesis.
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ANGPTL3 inhibition accelerates triglyceride-rich lipoprotein processing and reduces LDL precursors while enhancing HDL catabolism.
“In contrast, ANGPTL3 inhibition accelerates triglyceride-rich lipoprotein processing and reduces LDL precursors while enhancing HDL catabolism, accounting for concurrent LDL-C reduction and modest HDL-C decrease (Zhang, 2021; Chen et al., 2024; Adam et al., 2020; Wang et al., 2015; Yasuda et al., 2010; Hooper and Burnett, 2013).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Zhang, 2021
The Rationale (page not provided) explains that reducing ANGPTL3 inhibition permits LPL to hydrolyze circulating triglycerides and EL to hydrolyze HDL phospholipids. The Weaknesses section (page not provided) reports that ANGPTL3 antagonism lowers TG, LDL-C, and HDL-C in humans. Neither section says it reduces LDL precursors, and the paper does not characterize the HDL-C decrease as modest. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOC3 inhibition primarily enhances peripheral clearance of triglyceride-rich lipoproteins without substantially affecting hepatic VLDL production or LDL metabolism.
“APOC3 inhibition primarily enhances peripheral clearance of triglyceride-rich lipoproteins without substantially affecting hepatic VLDL production or LDL metabolism, explaining neutral LDL-C effects and a tendency toward higher HDL-C levels (Malick et al., 2023b; Zhang, 2021; Visser et al., 2022; Khetarpal et al., 2017; Chen et al., 2024).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Zhang, 2021
The Rationale and Weaknesses sections discuss ANGPTL3 and ANGPTL8, not APOC3. Searches for APOC3, apolipoprotein C-III, VLDL production, and LDL metabolism found no passage addressing the attributed mechanism or its claimed LDL-C and HDL-C effects. (LLM, conf=0.75)
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- Authors
- Zhang, R.
- Affiliations
- Wayne State University (US)
- Corresponding author
- Zhang, Ren
- ORCID
- Zhang, Ren
- Venue
- Frontiers in Cardiovascular Medicine
- Publisher
- Frontiers Media SA
- Published
- 2021-11-16
- Volume
- 8
- Pages
- 795370-795370
- ISSN
- 2297-055X (ISSN-L)
- PMC
- PMC8635044
- OpenAlex
- W3214719256
- Cited by
- 15
- References
- 15
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 1
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cardiovascular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (5R01HL134787)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- ANGPTL8, ANGPTL3, lipoprotein lipase, endothelial lipase, HDL cholesterol, atherosclerosis, cardiovascular disease
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