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Blood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive.Here, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism.We elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status.A lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels.Taken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Context: Recent studies have discovered a role of apolipoprotein M (apoM) in energy metabolism, and observational analyses in humans suggest an association with type 2 diabetes. The causal relationship remains however elusive.Objective: To investigate whether reduced plasma apoM concentrations are causally linked to increased risk of type 2 diabetes.Design: Prospective study design analyzed by Mendelian randomization.Setting and participants: Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants from the CCHS with available plasma apoM (n = 725). Genetic analyses included the complete cohorts (n = 102 446). During a median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes.Main outcome measures: Plasma apoM concentration, genetic variants in APOM, and type 2 diabetes.Results: First, we identified an inverse correlation between plasma apoM and risk of type 2 diabetes in a subset of participants from the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polymorphisms in APOM further revealed a 10.8% (P = 6.2 x 10(-5)) reduced plasma apoM concentration in participants with variant rs1266078. Third, a meta-analysis including data from 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes.Conclusions: The present study does not appear to support a causal association between plasma apoM and risk of type 2 diabetes.

Diabetic patients suffer from both cardiac lipid accumulation and an increased risk of arrhythmias and sudden cardiac death. This correlation suggests a link between diabetes induced cardiac steatosis and electrical abnormalities, however, the underlying mechanism remains unknown. We previously showed that cardiac conduction velocity slows in Zucker diabetic fatty rats and in fructose-fat fed rats, models that both exhibit prominent cardiac steatosis. The aim of this study was to investigate whether acute cardiac lipid accumulation reduces conduction velocity per se. Cardiac lipid accumulation was induced acutely by perfusing isolated rat hearts with palmitate-glucose buffer, or subacutely by fasting rats overnight. Subsequently, longitudinal cardiac conduction velocity was measured in right ventricular tissue strips, and intramyocardial triglyceride and lipid droplet content was determined by thin layer chromatography and BODIPY staining, respectively. Perfusion with palmitate-glucose buffer significantly increased intramyocardial triglyceride levels compared to perfusion with glucose (2.16 ± 0.17 (n = 10) vs. 0.92 ± 0.33 nmol/mg WW (n = 9), P < 0.01), but the number of lipid droplets was very low in both groups. Fasting of rats, however, resulted in both significantly elevated intramyocardial triglyceride levels compared to fed rats (3.27 ± 0.43 (n = 10) vs. 1.45 ± 0.24 nmol/mg WW (n = 10)), as well as a larger volume of lipid droplets (0.60 ± 0.13 (n = 10) vs. 0.21 ± 0.06% (n = 10), P < 0.05). There was no significant difference in longitudinal conduction velocity between palmitate-glucose perfused and control hearts (0.77 ± 0.025 (n = 10) vs. 0.75 m/sec ± 0.029 (n = 9)), or between fed and fasted rats (0.75 ± 0.042 m/sec (n = 10) vs. 0.79 ± 0.047 (n = 10)). In conclusion, intramyocardial lipid accumulation does not slow cardiac longitudinal conduction velocity per se. This is true for both increased intramyocardial triglyceride content, induced by palmi

Psoriasis is a chronic inflammatory skin disorder associated with several comorbidities, including atherosclerosis. Disease mechanisms that may affect both psoriasis and atherosclerosis include activation of T helper 1 and T helper 17 cells. Imiquimod application is an established mouse model of psoriasis-like skin inflammation. The cardiac glycoside digoxin inhibits the master transcription factor of T helper 17 differentiation, retinoid acid receptorrelated orphan nuclear receptor gamma t, and attenuates IL-17dependent pathologies in mice. We investigated whether cyclic imiquimod-induced psoriasis-like skin inflammation affects atherosclerosis in low-density lipoprotein receptordeficient mice and whether digoxin modifies either disease. Topical imiquimod application increased ear thickness, keratinocyte proliferation, and accumulation of CD3(+) T cells in the skin of low-density lipoprotein receptordeficient mice. Also, imiquimod affected the mice systemically with induction of splenomegaly as well as increased plasma levels of IL-17A and serum amyloid A. Overall, imiquimod reduced atherosclerosis in the aortic arch en face, but it did not affect atherosclerosis in the aortic root. Digoxin significantly reduced the imiquimod-induced ear thickening, had divergent effects on imiquimod-induced systemic inflammation, and did not affect atherosclerosis. In conclusion, cyclic imiquimod applications can be used for long-term induction of psoriasis-like skin lesions, but they attenuate atherosclerosis in low-density lipoproteindeficient mice. In this model, digoxin reduces skin inflammation, but it has no effect on atherosclerosis.