Early obesity leads to increases in hepatic arginase I and related systemic changes in nitric oxide and l-arginine metabolism in mice

Abstract

Obesity is a risk factor for vascular endothelial cell dysfunction characterized by low-grade, chronic inflammation. Increased levels of arginase I and concomitant decreases in L-arginine bioavailability are known to play a role in the pathogenesis of vascular endothelial cell dysfunction. In the present study, we focused on changes in the systemic expression of arginase I as well as L-arginine metabolism in the pre-disease state of early obesity prior to the onset of atherosclerosis. C57BL/6 mice were fed a control diet (CD; 10% fat) or high-fat diet (HFD; 60% fat) for 8 weeks. The mRNA expression of arginase I in the liver, adipose tissue, aorta, and muscle; protein expression of arginase I in the liver and plasma; and systemic levels of L-arginine bioavailability and NO were assessed. HFD-fed mice showed early obesity without severe disease symptoms. Arginase I mRNA and protein expression levels in the liver were significantly higher in HFD-fed obese mice than in CD-fed mice. Arginase I levels were slightly increased, whereas L-arginine levels were significantly reduced, and these changes were followed by reductions in NO levels. Furthermore, hepatic arginase I levels positively correlated with plasma arginase I levels and negatively correlated with L-arginine bioavailability in plasma. These results suggested that increases in the expression of hepatic arginase I and reductions in plasma L-arginine and NO levels might lead to vascular endothelial dysfunction in the pre-disease state of early obesity.

Effects of Three-Month Administration of High-Saturated Fat Diet and High-Polyunsaturated Fat Diets with Different Linoleic Acid (LA, C18:2n–6) to α-Linolenic Acid (ALA, C18:3n–3) Ratio on the Mouse Liver Proteome

“…Similar results were obtained in the study of Bashir et al where ARG1 protein and mRNA levels were reduced in murine macrophages in adipose tissue of the group fed an HFD in comparison to the lean group fed standard chow [ 59 ]. L-Arginine (Arg), hydrolyzed by arginase, is considered an important amino acid in homeostasis maintenance, and its metabolism is altered in various diseases [ 60 ]. Arginase I (ARG1) is the most abundantly expressed isoform in hepatocytes.…”

Obesity and asthma

“…This in turn reduces airway NO bioavailability and the airway's ability to bronchodilate normally. [66][67][68][69] Airway concentrations of asymmetric dimethyl arginine are greater in asthmatic adults and children when compared with controls, and L-arginine levels are lower in otherwise healthy obese and overweight subjects. [70][71][72] Obese patients with late-onset asthma in the Severe Asthma Research Program who had decreased Larginine to asymmetric dimethyl arginine ratios were noted to have increased respiratory symptoms, reduced lung function, lower IgE levels, and reduced fractional exhaled nitric oxide.…”

L-Citrulline increases nitric oxide and improves control in obese asthmatics

“…In addition, this phenotype is also characterized by having increased airway and systemic oxidative stress biomarkers (26,28), which may be associated with increased corticosteroid resistance. Regardless of body weight, airway concentrations of ADMA are greater in asthmatic adults and children when compared with controls, and L-arginine levels are lower in otherwise healthy obese and overweight subjects (29)(30)(31)(32). Therefore, it is not surprising that the convergence of these 2 chronic diseases lowers the L-arginine/ADMA balance, uncoupling airway epithelial NOS (5).…”