NO synthesis from arginine is favored by a-linolenic acid in mice fed a high-fat diet

Key Findings

Metabolic syndrome (MetSynd) is a cluster of abnormalities, including visceral obesity, dyslipidemia, hyperglycemia, and increased blood pressure, which results in a higher risk of cardiovascular diseases and type-2 diabetes. A decrease in nitric oxide (NO) synthesis and changes in the metabolism of arginine have been proposed as being central to the initiation of MetSynd.  The NO synthase (NOS) and arginase pathways compete for arginine. In this research, the effects of ALA on arginine–NO pathway in a dietary model of early MetSynd, induced in mice fed high-fat diets providing either SFA or ALA was assessed. ALA fed mice had a higher plasma nitrite and nitrate concentration, a higher whole-body conversion of arginine into NO. The data suggests that ALA may improve dysfunctions associated with the early initiation of MetSynd. The mechanism of action may involve arginine metabolism in extra-hepatic tissues and the vascular endothelium.

Abstract

Alterations in NO availability and signaling play a pivotal role at early stages of the metabolic syndrome (MetSynd). We hypothesized that dietary α-linolenic acid (ALA, 18:3 n-3) favors NO availability by modulating amino acid metabolism, with a specific impact on the arginine-NO pathway. Mice were fed a hyperlipidic diet (285 g lipid/kg, 51.1 % energy), rich in either saturated fatty acids (SFA, provided by palm oil, PALM group) or ALA (provided by linseed oil, LIN group). We measured whole-body NO synthesis and systemic arginine hydrolysis with a tracer-based method, plasma concentration of related metabolites, and hepatic mRNA level of related enzymes, and the study was completed by a transcriptomic analysis in the liver. As expected with this model, hyperlipidic diets resulted in increased adiposity and glycemia after 5 weeks. As compared to PALM mice, LIN mice had a higher plasma nitrite and nitrate concentration, a higher whole-body conversion of arginine into NO vs urea, and a similar plasma concentration of asymmetric dimethylarginine (ADMA), despite a higher expression of the liver dimethylargininase-1. In LIN mice, there was a higher expression of genes involved in PPARα signaling, but a little impact on gene expression related to amino acids and arginine metabolism. This effect cannot be directly ascribed to changes in arginase activity in the liver or ADMA metabolism, nor to direct regulation of the related target genes. In conclusion, dietary ALA favors NO synthesis, which could contribute to rescue NO availability when jeopardized by the nutritional conditions in relation with the initiation of the MetSynd