👤 Małgorzata Trocha

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like particle that contains a unique apolipoprotein(a) [apo(a)] component covalently bound to apolipoprotein B-100. Elevated levels of Lp(a) have been identified as a well-established and genetically determined risk factor for atherosclerotic cardiovascular disease, including coronary artery disease, stroke, and calcific aortic valve stenosis. In contrast to other lipids, Lp(a) concentrations are minimally influenced by lifestyle or traditional lipid-lowering therapies, emphasizing the necessity for novel treatment approaches. This narrative review summarizes current and emerging therapeutic strategies for reducing Lp(a) levels. Such strategies include traditional agents such as niacin and PCSK9 inhibitors, as well as innovative therapies such as antisense oligonucleotides, RNA interference-based molecules, and small-molecule inhibitors. The mechanisms of action of these agents, in addition to clinical trial data and their capacity to modify cardiovascular outcomes, are explored in further detail. Furthermore, the current status of clinical guidelines and the evolving role of Lp(a)-targeted therapies in cardiovascular risk stratification are reviewed. A particular emphasis is placed on therapies that are in the advanced stages of clinical development. These include late-phase outcome trials and orally administered agents, which have the potential to significantly impact future clinical practice. The integration of mechanistic data with ongoing and completed clinical studies has been undertaken in order to provide a comprehensive framework for understanding the therapeutic potential of Lp(a) in the context of cardiovascular prevention. Show less

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation-related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid-sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid-responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4-6 weeks of reduced protein intake (7%-9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia. Show less