Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Abstract

Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.

C3 and alternative pathway components are associated with an adverse lipoprotein subclass profile: The CODAM study

“…C3adesarg/ASP may contribute to the synthesis of TG 27,28 and subsequently increase the formation and accumulation of TG-enriched lipoproteins, which contribute to the formation of atherogenic small dense LDL. 29 The lack of association of C3a with lipoprotein characteristics in our current data does not support this explanation, unless such a process would be constrained to the interstitial compartment and not be reflected at the systemic level.…”

The beneficial effects of virgin olive oil against oxidative stress induced by hypercholesterolemia in rats

“…An improved oxidative status due to the consumption of olive oil polyphenols may counteract increases in LDL concentrations by decreasing the number of small LDL particles. Second, increases in the expression of LPL may help the organism to decrease concentrations of TG-rich lipoproteins (e.g., LDLs), because LPL is the main enzyme involved in the removal of TGs from the blood and presents some LDL receptor activity (Reiner, 2018). Finally, improvements in general oxidative status have been associated with a better activity of LPL (Hernaez et al, 2015).…”

Novel Experimental Agents for the Treatment of Hypercholesterolemia

“…While the debate whether lowering of serum triglycerides (TGs) does produce any benefits is still ongoing, 40 , 41 new drugs are being developed that act on TGs. Namely, the results of some authors clearly showed that in patients with residual risk for ASCVD with elevated TGs levels, TGs are at least an independent marker for an increased risk of ischemic events as shown by Mendelian randomization studies.…”