👤 Christian Schlein

Thoracic aortic aneurysms frequently go undetected until serious complications like acute dissections or ruptures arise. Therefore, this study aims to identify potential blood circulating biomarkers enabling an easy and early diagnosis of thoracic aortic disease. Potential biomarker candidates were identified through two different techniques, untargeted and targeted proteomic as well as extracellular vesicle (EV) analyses. The biomarker levels were compared between two patient groups with thoracic aortic aneurysms and two control groups without thoracic aortic disease. In total, 80 patients (TAA group (n = 40) vs. control group (n = 40)) were matched for untargeted and targeted proteome analysis, and 85 for EV analysis (TAA group (n = 42) vs. control group (n = 43)), based on the availability of blood samples and excised aortic tissue. Levels of biomarker candidates were correlated with aortic diameter, patient age, and histological alterations in aortic tissue using linear and logistic regression models. The untargeted proteomic and EV analysis identified 1,037 and 1,077 proteins, respectively, of which 11 and 28 proteins showed significant differences in concentration between the study groups. Of these, 9 proteins correlated with the aortic diameter: ACTN1 (Regression coefficient B = 1.633, p < 0.001), CRP (B = 0.001, p = 0.004), TGM3 (B=-0.293, p = 0.010), KRT84 (B=-0.477, p = 0.010), IGHG3 (-0.267, p = 0.018), DPYSL2 (B = 0.644, p = 0.020), TSPAN8 (B-0.838, p = 0.042), IGKV3D-11 (B=-0.242, p = 0.046), and VDAC1 (B=-0.491, p = 0.047). Moreover, IGKV3D-11 (B=-3.257, p = 0.029), IGHG3 (B=-0.003, p = 0.034), and APOC3 (B=-2.104, p = 0.037) showed significant correlations with the grade of aortic medial layer degeneration. None of the proteins correlated with patient age. The study identified 9 biomarker candidates correlating with the aortic diameter. To enable the clinical use for diagnosis and prognostic assessment, these biomarkers need to be validated in larger external cohorts. Show less

Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment. 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