In mouse models, apolipoprotein A-V (apoA-V) exhibits triglyceride (TG)-lowering effects. We investigated the apoA-V/TG relationship and the association of apoA-V with coronary artery disease (CAD) risk by determining serum apoA-V levels and genotypes in a nested case-control (n 5 1,034/2,031) study. Both univariate and multivariate apoA-V levels showed no association with future CAD (P 5 0.4 and 0.5, respectively). Unexpectedly, there was a significant positive correlation between serum apoA-V and TG in men and women (r 5 0.36 and 0.28, respectively, P , 0.001 each) but a negative correlation between apoA-V and LPL mass (r 5 20.14 and 20.12 for men and women respectively, P , 0.001 each). The frequency of the c.56C.G polymorphism did not differ between cases and controls despite significant positive association of c.56G with both apoA-V and TG levels. For 21131T.C, the minor allele was significantly associated with lower apoA-V yet higher TG levels and was overrepresented in cases (P 5 0.047). The association of 21131T.C with CAD risk, however, was independent of apoA-V levels and likely acts through linkage disequilibrium with APOC3 variants. The positive correlation of apoA-V levels with TG levels, negative correlation with LPL levels, and lack of association with CAD risk highlight the need for further human studies to clarify the role of apoA-V.-Vaessen, S.

Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to characterize better available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine, and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum; = 4), in human intestine (jejunum; = 9), and Caco-2 cells. Expression of the included transporters and enzymes was in general well comparable between porcine and human intestinal tissue, although breast cancer resistance protein, monocarboxylate transporter 5, multidrug resistance protein (MRP) 1, MRP1, MRP3 (∼2-fold), and organic anion-transporting polypeptide (OATP) 4A1 (∼6-fold) was higher expressed in pig compared with human jejunum. Alternatively, expression level of relevant transporter proteins (glucose transporter 1, OATP4A1, MRP2, MRP1, and OATP2B1) was significantly higher (3- to 130-fold) in Caco-2 cells compared with human jejunum. Moreover, all examined CYPs showed at least a fivefold lower gene expression in Caco-2 cells compared with human jejunum, with the smallest differences for CYP1A1 and CYP3A5 and the largest difference for CYP3A4 (871-fold higher expression in human jejunum compared with Caco-2 cells). In conclusion, a comprehensive overview is provided of the expression levels of clinically relevant transporter proteins and metabolic enzymes in porcine and human intestinal tissue and Caco-2 cells, which may assist in deciding upon the most suitable model to further improve our understanding of processes that determine intestinal absorption of compounds.

The relevance of apolipoprotein A-V (apoA-V) for human lipid homeostasis is underscored by genetic association studies and the identification of truncation-causing mutations in the APOA5 gene as a cause of type V hyperlipidemia, compatible with an LPL-activating role of apoA-V. An inverse correlation between plasma apoA-V and triglyceride (TG) levels has been surmised from animal data. Recent studies in human subjects using (semi)quantitative immunoassays, however, do not provide unambiguous support for such a relationship. Here, we used a novel, validated ELISA to measure plasma apoA-V levels in patients (n 5 28) with hypertriglyceridemia (HTG; 1.8-78.7 mmol TG/l) and normolipidemic controls (n 5 42). Unexpectedly, plasma apoA-V levels were markedly increased in the HTG subjects compared with controls (1,987 vs. 258 ng/ml; P , 0.001). In the HTG group, apoA-V and TG were positively correlated (r 5 10.44, P 5 0.02). In addition, we noted an increased level of the LPL-inhibitory protein apoC-III in the HTG group (45.8 vs. 10.6 mg/dl in controls; P , 0.001). The correlation between apoA-V and TG levels in the HTG group disappeared (partial r 5 10.09, P 5 0.65) when controlling for apoC-III levels. In contrast, apoC-III and TG remained positively correlated in this group when controlling for apoA-V (partial r 5 10.43, P 5 0.025). Our findings suggest that in HTG patients, increased TG levels are accompanied by high plasma levels of apoA-V and apoC-III, apolipoproteins with opposite modes of action. This study provides evidence for a complex interaction between apoA-V and apoC-III in patients with severe HTG. The recognition of hypertriglyceridemia (HTG) as an independent risk factor for cardiovascular pathologies (1) necessitates the identification of the factors involved in the regulation of plasma triglyceride (TG) levels. Along with esterified cholesterol, TGs constitute the neutral lipid core of chylomicrons, VLDL, and their remnants. LPL is the principal enzyme involved in the degradation of TG in plasma. The hydrolytic action of LPL requires the presence of a cofactor [i.e., apolipoprotein C-II (apoC-II)] and is modulated by a number of other factors (2-4). Important negative regulators are apoC-III and the recently identified angiopoietin-like proteins ANGPTL3 and ANGPTL4 (3,(5)(6)(7). In addition to these negative effectors, the novel apolipoprotein apoA-V was identified as a positive effector of LPL activity (8-10).ApoA-V has readily become recognized as an important determinant of plasma TG levels in humans and mice since its discovery 5 years ago (11,12). Animal experiments using different strategies of underexpression and overexpression indicated an inverse relationship between apoa5 gene expression and plasma TG (11, 13) [e.g., adenoviral expression of apoa5 in mice resulted in a dose-dependent reduction of plasma TG levels (9)]. In humans, genetic variation at the APOA5 locus has been associated with HTG (11,[14][15][16][17]. Moreover, homozygosity for truncation-causing mutations (Q148X and Q...

CD2F1 mice were inoculated with C26 adenocarcinoma cells, followed by assessment of ex vivo muscular function. Muscles from tumor-bearing mice had a significantly lower force output during a single maximal contraction and during repeated contractions than control muscles. The relative force output, however, did not differ when corrected for muscle mass. Thus, cachexia significantly reduces absolute skeletal muscle function, but muscle "quality" appears unaltered.