ANGPTL3 Inhibition Could Protect Against Coronary Artery Disease

Health, Fitness & Food


New studies demonstrate that inhibiting the activity of angiopoietin-like 3 (ANGPTL3), a liver protein that regulates lipoprotein metabolism and inhibits lipoprotein lipase (LPL), could help lower the plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol as well as reduce the risk of atherosclerotic coronary artery disease.

 

It has been observed that coronary artery disease patients are at risk for heart attacks and strokes even after being put on LDL cholesterol-lowering medication, such as the statins orezetimibe. Many such patients show high plasma levels of triglyceride-rich lipoproteins. The levels of triglyceride-rich lipoproteins are regulated by an enzyme called lipoprotein lipase, which breaks down the triglycerides in lipoproteins to fatty acids and glycerol and helps deliver them to the muscle and fatty tissue. ANGPTL3 is known to inhibit lipoprotein lipase and is associated with high plasma levels of triglyceride-rich lipoproteins. Individuals carrying mutations in both copies of the ANGPTL3 gene that render it dysfunctional are known to have significantly reduced levels triglyceride-rich lipoproteins, LDL cholesterol, and HDL cholesterol in a condition called familial combined hypolipidemia.

The plasma levels of ANGPTL3 are also known to be linked to the thickness of the inner walls of arteries, which in turn is known to be associated with high blood pressure and high lipid levels.1Therefore, inhibiting ANGPTL3 activity represents a way of lowering lipid levels in the blood and possibly, lowering the risk of atherosclerotic coronary artery disease. Now, two teams of researchers show that this could indeed be the case in two separate papers published in a recent issue of The New England Journal of Medicine.2-4

In one study, the researchers sequenced the exons (regions of DNA that are transcribed into RNA and eventually form part of the protein) of the ANGPTL3 gene from 58,335 individuals who participated in the study.3 They found that individuals with mutations in the ANGPTL3 gene that resulted in dysfunctional protein had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol. The researchers then tested the effects of evinacumab, an antibody that binds to the ANGPTL3 protein and inhibits its activity, in mice and healthy humans with high levels of triglycerides or LDL cholesterol. In mice, evinacumab reduced atherosclerotic plaque areas in the aorta, whereas, in humans, evinacumab caused a dose-dependent reduction in fasting triglyceride and LDL cholesterol levels of up to 76% and 23%, respectively.

In the second study, antisense oligonucleotides were used in mice to block the translation of the Angptl3 RNA into protein, and the effects of blocking ANGPTL3protein production on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis were examined.4 The researchers also examined the effects of subcutaneously injecting antisense ANGPTL3 RNA into healthy human subjects who received different doses of the drug depending on their fasting triglyceride levels. The mice treated with the antisense mRNA had lower levels of triglycerides and LDL cholesterol, increased insulin sensitivity, and slow-down in atherosclerosis. In humans, there was a significant reduction in the levels of triglyceride, LDL cholesterol, VLDL cholesterol, nonhigh-density lipoprotein cholesterol, apolipoprotein B, and apolipoprotein C-III.

In a third study published in the same issue of the journal, another group of researchers reports that when combined with existing cholesterol-lowering drugs, a single dose of the anti-ANGPTL3antibody could lower LDL cholesterol levels by an additional 49% in individuals with homozygous familial hypercholesterolemia, which is caused by mutations in the LDLR gene.5

Therefore, enhancing the activity of lipoprotein lipase by targeting its inhibitor ANGPTL3 is a promising new approach for lowering plasma lipid levels and treating hypertriglyceridemia and atherosclerotic coronary artery disease that may make the journey from the lab bench to the bedside in the years to come.

Written by Usha B. Nair, Ph.D.

References:

  1. Hatsuda S, Shoji T, Shinohara K, Kimoto E, Mori K, Fukumoto S, Koyama H, Emoto M, Nishizawa Y. Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects. J Vasc Res. 2007;44(1):61-6. Epub 2006 Dec 21. PubMed PMID: 17191020.
  2. Tall AR. Increasing Lipolysis and Reducing Atherosclerosis. N Engl J Med. 2017 Jul 20;377(3):280-283. doi: 10.1056/NEJMe1706907. PubMed PMID: 28723326.
  3. Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 Jul 20;377(3):211-221. doi: 10.1056/NEJMoa1612790. Epub 2017 May 24. PubMed PMID: 28538136.
  4. Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, et al. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017 Jul 20;377(3):222-232. doi: 10.1056/NEJMoa1701329. Epub 2017 May 24. PubMed PMID: 28538111.
  5. Gaudet D, Gipe DA, Pordy R, Ahmad Z, Cuchel M, Shah PK, et al., ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. N Engl J Med. 2017 Jul 20;377(3):296-297. doi: 10.1056/NEJMc1705994. PubMed PMID: 28723334.

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