This article is available online at http://www.jlr.org Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the Western world ( 1 ). Elevated levels of LDL-cholesterol (LDL-C) have consistently shown a positive association with the development of CVD, justifying the current therapeutic strategies to prevent CVD primarily by the use of statins. Members of this drug class inhibit HMG-CoA reductase (HMGR), the rate-limiting enzyme for de novo cholesterol synthesis, thereby leading to decreased LDL-C ( 2-4 ). While the benefi ts of statins have been documented ( 2 ), many individuals on statin therapy still remain at a higher risk of developing CVD. It is possible this residual risk is a result of other metabolic syndrome (MetS) risk factors characterized by dyslipidemia and insulin resistance and is also in part due to statin intolerance ( 5-7 ) and noncompliance often related to statininduced myalgia ( 8, 9 ). Statins are effective at decreasing LDL-C and CVD; however, frequent muscle-related side effects limit dosage and impede maximal risk reduction in dyslipidemic patients ( 10 ). Furthermore, recent evidence suggests that high-dose statins may increase the risk of developing type 2 diabetes (T2D) ( 11 ), further justifying the need for alternative therapeutic interventions that have statin-like effects for lowering LDL-C and are designed to Abstract ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid  -oxidation. However, the molecular mechanism(s) mediating these activities remained undefi ned.
The glucagon-like peptides (GLP-1 and GLP-2) are processed from the proglucagon polypeptide and secreted in equimolar amounts but have opposite effects on chylomicron (CM) production, with GLP-1 significantly reducing and GLP-2 increasing postprandial chylomicronemia. In the current study, we evaluated the apparent paradoxical roles of GLP-1 and GLP-2 under physiological conditions in the Syrian golden hamster, a model with close similarity to humans in terms of lipoprotein metabolism. A short (30-min) intravenous infusion of GLP-2 resulted in a marked increase in postprandial apolipoprotein B48 (apoB48) and triglyceride (TG) levels in the TG-rich lipoprotein (TRL) fraction, whereas GLP-1 infusion decreased lipid absorption and levels of TRL-TG and apoB48. GLP-1 and GLP-2 coinfusion resulted in net increased lipid absorption and an increase in TRL-TG and apoB48. However, prolonged (120-min) coinfusion of GLP-1 and GLP-2 decreased postprandial lipemia. Blocking dipeptidyl peptidase-4 activity resulted in decreased postprandial lipemia. Interestingly, fructose-fed, insulin-resistant hamsters showed a more pronounced response, including possible hypersensitivity to GLP-2 or reduced sensitivity to GLP-1. In conclusion, under normal physiological conditions, the actions of GLP-2 predominate; however, when GLP-1 activity is sustained, the hypolipidemic action of GLP-1 predominates. Pharmacological inhibition of GLP-1 degradation tips the balance toward an inhibitory effect on intestinal production of atherogenic CM particles.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.