👤 Denis Sviridov

Apolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformation of lipoprotein lipase (LPL). LPL unfolding results in loss of catalytic activity and the detachment of LPL from the surface of cells. An Show less

We previously reported that Oxy210, an oxysterol-based drug candidate, exhibits antifibrotic and anti-inflammatory properties. We also showed that, in mice, it ameliorates hepatic hallmarks of non-alcoholic steatohepatitis (NASH), including inflammation and fibrosis, and reduces adipose tissue inflammation. Here, we aim to investigate the effects of Oxy210 on atherosclerosis, an inflammatory disease of the large arteries that is linked to NASH in epidemiologic studies, shares many of the same risk factors, and is the major cause of mortality in people with NASH. Oxy210 was studied in vivo in APOE*3-Leiden.CETP mice, a humanized mouse model for both NASH and atherosclerosis, in which symptoms are induced by consumption of a high fat, high cholesterol "Western" diet (WD). Oxy210 was also studied in vitro using two cell types that are important in atherogenesis: human aortic endothelial cells (HAECs) and macrophages treated with atherogenic and inflammatory agents. Oxy210 reduced atherosclerotic lesion formation by more than 50% in hyperlipidemic mice fed the WD for 16 weeks. This was accompanied by reduced plasma cholesterol levels and reduced macrophages in lesions. In HAECs and macrophages, Oxy210 reduced the expression of key inflammatory markers associated with atherosclerosis, including interleukin-1 beta ( These findings suggest that Oxy210 could be a drug candidate for targeting both NASH and atherosclerosis, as well as chronic inflammation associated with the manifestations of metabolic syndrome. Show less

Defects in lipolysis can lead to hypertriglyceridemia, which can trigger acute pancreatitis and is also associated with cardiovascular disease. Decreasing plasma triglycerides (TGs) by activating lipoprotein lipase (LPL) with ApoC2 mimetic peptides is a new treatment strategy for hypertriglyceridemia. We recently described a dual ApoC2 mimetic/ApoC3 antagonist peptide called D6PV that effectively lowered TG in several mouse models but has limitations in terms of drug development. The aim of this study was to create the next generation of ApoC2 mimetic peptides. We employed hydrocarbon staples, as well as select amino acid substitutions, to make short single helical mimetic peptides based on the last helix of ApoC2. Peptides were first tested for their ability to activate LPL and then in hypertriglyceridemia mouse models. All-atom simulations of peptides were performed in a lipid-trilayer model of TG-rich lipoproteins to discern their possible mechanism of action. We designed a single stapled peptide called SP1 (21 residues), and a double stapled (stitched) peptide called SP2 (21 residues) and its N-terminal acylated analogue, SP2a. The hydrocarbon staples increased the amphipathicity of the peptides and their ability to bind lipids without interfering with LPL activation. Indeed, from all-atom simulations, the conformations of SP1 and SP2a are restrained by the staples and maintains the proper orientation of the LPL activation motif, while still allowing their deeper insertion into the lipid-trilayer model. Intraperitoneal injection of stapled peptides (1-5 umoles/kg) into ApoC2-hypomorphic mice or human ApoC3-transgenic resulted in an 80%-90% reduction in plasma TG within 3 h, similar to the much longer D6PV peptide (41 residues). Other modifications (replacement L-Glu20, L-Glu21 with their D-isomers, N-methylation of Gly19, Met2NorLeu and Ala1alpha-methylAla substitutions, N-terminal octanoylation) were introduced into the SP2a peptide. These changes made SP2a highly resistant to proteolysis against trypsin, pepsin, and Proteinase K, while maintaining similar efficacy in lowering plasma TG in mice. We describe a new generation of ApoC2 mimetic peptides based on hydron carbon stapling that are at least equally potent to earlier peptides but are much shorter and resistant to proteolysis and could be further developed into a new therapy for hypertriglyceridemia. Show less