DIETARY CHOLINE INCREASES PLASMA CONCENTRATION OF GUT-DERIVED UREMIC TOXINS AND METABOLITES ASSOCIATED WITH CHRONIC KIDNEY DISEASE PROGRESSION IN APOE-KNOCKOUT MICE WITH ELEVATED HDL

Background and Aims: Experimental and observational studies have highlighted a positive correlation between increased plasma concentration of choline-derived trimethylamine-N-oxide (TMAO) and adverse cardiovascular events. This study was aimed at investigating how the plasma metabolome of mice prone to atherosclerosis development was modulated by HDL levels and the dietary intake of choline. Methods: Standard rodent diets with different choline content (0.09% or 1.2%) were administered for 16 weeks to two groups of atherosclerosisprone female mice: 1) extremely low-HDL mice, deficient for both murine apoA-I and apoE (DKO); 2) high-HDL mice, deficient for both apoA-I/apoE, but overexpressing human apoA-I (DKO/hA-I). At sacrifice, atherosclerosis was evaluated, and a targeted metabolomics of plasma was performed. Results: Atherosclerosis development evaluated at the aortic sinus, was strongly increased in DKO vs DKO/hA-I mice. Surprisingly, although the high-choline diet resulted into elevated plasma TMAO levels in both genotypes, choline supplementation significantly worsened plaque development only in DKO/hA-I mice. Noteworthy, high-choline diet led to an increased concentration of plasma lipids only in DKO/hA-I mice: mainly total cholesterol, but also ceramides and hexosylceramides. Several markers of increased cardiovascular disease risk and chronic kidney disease progression such as the gut-derived uremic toxins phenyacetylglutamine and indoxyl sulfate and plasma metabolites asymmetric dimethylarginine, symmetric dimethylarginine and acetylcarnitine were increased only in high-choline-fed DKO/hA-I mice. Conclusions: Dietary choline supplementation worsens atherosclerosis development only in the presence of HDL. Plasma metabolomics clearly indicated that choline supplementation increases the concentration of different lipid classes as well as of different metabolites indicative of augmented cardiovascular risk and impaired kidney function.