👤 Rudolf Merkel

Brain vascular aging is increasingly recognized as a critical therapeutic target for age-related cognitive decline. Oxidative stress, bioenergetic dysfunction, and molecular damage play central roles in the progression of vascular aging, contributing to cerebrovascular dysfunction and impaired cognitive function. While naturally occurring polyphenols such as resveratrol (RSV) have demonstrated potential in mitigating aging-related pathologies, their poor bioavailability and limited brain targeting efficiency significantly constrain their therapeutic impact. As a result, high doses or advanced drug delivery strategies are necessary to achieve meaningful physiological effects. We introduce a novel nanocarrier system designed to enhance RSV delivery to the cerebral endothelium by leveraging the natural formation of an apolipoprotein E (ApoE)-enriched protein corona around fusogenic liposomes (FL) Show less

Deficiency of apoprotein A-V (apoA-V) can cause hypertriglyceridemia. In an 11 months old boy presenting with a severe hypertriglyceridemia, a formerly unknown 24 nucleotide deletion in exon 2 of the APOA5 gene was detected. The homozygous mutation results in an eight amino acid loss in the signal peptide sequence (c.16₃₉del; p.Ala6_Ala13del). Screening of control persons proved that this deletion is a rare mutation. Hypertriglyceridemia in the patient was only found at the time when he was breast fed, while after weaning, triglyceride levels were close to normal. Under both dietary conditions, apoA-V protein was undetectable in plasma while post-heparin plasma lipoprotein lipase activity was normal. Expression analysis of normal and mutated protein by Western blot and immunofluorescence in apoA-V deficient primary hepatocytes revealed that, due to changes in the signal peptide, mutated apoA-V was intracellularly missorted to lipid droplets and not secreted. Wild type apoA-V, instead, was not targeted to lipid droplets but transported via endosomal compartments to the plasma membrane for secretion. It is concluded that the c.16₃₉del mutation in the APOA5 gene leads to hepatic missorting and impaired secretion, which consequently results in undetectable apoA-V plasma levels. The absence of apoA-V in plasma leads under conditions of fat-rich diets to severe chylomicronemia, suggestive for a modulatory role of apoA-V for lipoprotein lipase mediated intravascular triglyceride lipolysis. Show less

Since its discovery, apolipoprotein A-V has been considered to be a potent factor affecting plasma triglycerides (TG) in humans and mice. Several single nucleotide polymorphisms in the APOA5 gene are associated with increased TG levels in humans, and some nonsense mutations affecting protein structure predispose for familial hypertriglyceridemia and late onset chylomicronemia. It is not clear, how apoA-V decreases plasma TG. There are three major hypotheses: apolipoprotein A-V could work through (1) an intracellular mechanism affecting VLDL production in the liver, (2) stimulation of proteoglycan-bound lipoprotein lipase at the endothelium of capillaries in peripheral organs, or (3) enhancing the clearance of TG-rich lipoproteins via lipoprotein receptors in the liver. There is good evidence for a role of apoA-V in extracellular TG metabolism and increasing support for an additional function of ApoA-V as a receptor ligand. The intracellular role of apoA-V for lipoprotein assembly and secretion is still speculative. This review discusses these possible mechanisms. Show less

The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -Delta139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (-25% [P=0.005], -36% [P<0.0001], and -23% [P=0.02]), respectively). ApoAV-C271, -X139, -X148, and Delta139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans, appears to be essential for their phenotypic expression. Show less

Apolipoprotein A-V (apoA-V) was discovered in 2001 both by comparative sequencing and as a liver regeneration protein. The gene is a located at the APOA1/C3/A4/A5 gene cluster on chromosome 11q23, a locus well known for playing a major role in regulating plasma cholesterol and triglyceride (TG) levels. ApoA-V is produced in the liver and has very low plasma concentrations (0.1-0.4 mug/ml). Mice lacking apoA-V have 4-fold increased TG levels, whereas apoA-V overexpression leads to 40% plasma TG reduction. Based on metabolic studies in vivo, apoA-V enhances the catabolism of TG rich lipoproteins rather than affecting their intestinal or hepatic production. By activating proteoglycans-bound lipoprotein lipase (LPL), apoA-V can accelerate TG hydrolysis from VLDL and chylomicrons independent from other apoproteins. Several variants at the APOA5 gene locus have been detected in humans. Some single nucleotide polymorphisms (SNPs) are associated with significantly higher plasma TG levels in patients (e.g., -1131T > C, S19W, G185C). In addition, these SNPs may affect fibrate response and obesity. However, data for a possible association of APOA5 variants with coronary heart disease are not consistent. Severe structural mutations (Q139X, Q148X, IVS3 + 3G > C) predispose to familial hypertriglyceridaemia and late-onset chylomicronaemia. Thus, despite its low plasma concentration, apoA-V is a major regulator of plasma TG metabolism in humans. However, the precise mechanism of its function is not yet clear. Show less

APOA5 is a newly identified apolipoprotein that plays a crucial role in the regulation of plasma triglyceride levels. In several human studies, common APOA5 single nucleotide polymorphisms have been strongly associated with elevated plasma triglyceride levels. In this issue of the JCI, Marçais et al. report that the rare Q139X mutation in APOA5 leads to severe hypertriglyceridemia by exerting a dominant-negative effect on the plasma lipolytic system for triglyceride-rich lipoproteins. The presented data support the idea that the molecular mechanism of APOA5 function may include the enhancement of binding between lipoproteins and proteoglycans at the vascular wall and activation of proteoglycan-bound lipoprotein lipase. Show less

Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis. Show less