Possible contribution of hepatocyte secretion to the elevation of plasma exosomal arginase-1 in high-fat diet-fed mice
Introduction
Obesity is a major risk factor for type 2 diabetes and cardiovascular disease and is considered an early stage of atherosclerosis [1,2]. One mechanism underlying atherosclerosis development is a decrease in nitric oxide (NO) levels, which is important for maintaining vascular homeostasis [3]. NO is synthesized by NO synthase (NOS) from L-arginine, which is also a substrate for arginase, an enzyme involved in the urea cycle. Thus, increased arginase activity consumes L-arginine, and decreases NO production by NOS. Therefore, the enzymatic activity of arginase is considered an important factor in the pathogenesis of obesity-induced atherosclerosis [4]. Two isoforms of arginase are known: arginase-1 is localized in the cytoplasm and is primarily expressed in the liver, whereas arginase-2 is localized in the mitochondria and is expressed in extrahepatic tissues [5]. Moreover, arginase activity in blood vessels reportedly increases in obesity-associated diabetes mellitus, atherosclerosis, and hypertension [6,7]. In a previous study involving healthy adults, we found that plasma arginase-1 levels, in addition to arginase activity, are positively correlated with body mass index and hemoglobin A1c (HbA1c) levels and are negatively correlated with L-arginine and NO levels [8,9]. Although these results indicate that plasma arginase activity may be dependent on plasma arginase-1, little is known about the mechanism underlying the increase in blood levels of the liver enzyme arginase-1. Therefore, we previously analyzed early obesity mice fed high-fat diet (HFD) for 8 weeks and found that, although there were no changes in arginase-1 mRNA levels in the adipose tissue, aorta, or muscles, it was markedly increased in the liver. Further, the plasma levels of arginase-1 levels tended to be higher, whereas L-arginine and NO levels were lower [10]. Therefore, in the present study, we analyzed obese model mice fed HFD for 12 weeks to investigate the mechanism of increase in the level of plasma arginase-1. Moreover, to investigate the relationship between blood glucose levels, plasma exosomal arginase-1 and arginase-1 expression in the liver, the human hepatocyte cell line HepG2 were analyzed for secreted exosomal arginase-1 after treatment with high glucose exposure.
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Animals
Three-week-old male C57/BL6J mice were obtained from Charles River Laboratories Japan (Yokohama, Japan) and were maintained under specific pathogen-free conditions with a 12-h light/12-h dark cycle and ad libitum access to food and tap water. HFD (D12492) and control diet (CD; D12450B) were purchased from Research Diets (New Brunswick, NJ, USA). The mice were acclimatized to these conditions for 1 week before initiation of the diets. The glucose levels in the blood obtained from the tail vein
HFD-fed mice exhibit decreased NO levels and increased L−arginine utilization due to increased activity of plasma arginase
HFD-fed mice exhibited higher body weight and higher blood glucose levels throughout the 12 weeks, compared to the CD-fed mice (Figs. 1A, S1). Neither the average water intake nor the average food intake, measured in terms of weight, differed significantly between these two groups, although the mean food intake, measured in terms of energy, was ~41% higher in the HFD-fed mice than that in the CD-fed mice (Fig. S1). Total plasma cholesterol, insulin levels and HOMA-IR were higher in the HFD-fed
Discussion
Results of the current study demonstrated that NO and L-arginine levels were decreased, while arginase activity was increased in the plasma of HFD-fed mice. Moreover, we showed that increased secretion of arginase-1, one of the isozymes of arginase, might contribute to the increase in plasma arginase activity in HFD-fed mice. This is a novel finding as, although previous animal model studies for atherosclerosis, diabetes, and obesity, have reported increased arginase in vascular tissues or
Conclusions
The pathway associated with exosomal arginase-1 secretion from the liver into the blood might be a new target for prevention of atherosclerosis in obesity.
Acknowledgments
We express our sincere gratitude to Dr. Yoshihisa Fujikura for his contribution to this study.
Funding
This work was supported by JSPS KAKENHI [grant numbers: 17K15977, 20K17067, 26293152, 24790587, 23390163, 15K08775].
Author contributions
Conceptualization; Masaru Harada, Narufumi Suganuma, Keiki Ogino, Koichiro Miyagawa;
Methodology; Kenjiro Nagaoka, Masamitsu Eitoku;
Validation; Noriyoshi Ogino;
Formal analysis; Hidekazu Takahashi, Masayuki Kubo;
Investigation; Noriyoshi Ogino, Yuki Harada, Hidekazu Takahashi, Masayuki Kubo;
Data curation; Noriyoshi Ogino, Hidekazu Takahashi, Masayuki Kubo;
Writing—original draft preparation; Noriyoshi Ogino;
Writing—review and editing; Keiki Ogino;
Supervision; Masaru Harada, Yuichi Honma, Masashi
Institutional review board statement
The care and handling of the animals were in accordance with the Guidelines for the Care and Use of Laboratory Animals at the Shikata Campus of Okayama University, and this study was approved by the Okayama University Institutional Animal Care and Use Committee (OKU-2012135).
Declaration of competing interest
The authors declare that there are no conflicts of interest.
References (29)
- et al.
Metabolic effects of dietary nitrate in health and disease
Cell Metab.
(2018) - et al.
Arginase: an old enzyme with new tricks
Trends Pharmacol. Sci.
(2015) - et al.
Evaluation of serum arginase I as an oxidative stress biomarker in a healthy Japanese population using a newly established ELISA
Clin. Biochem.
(2013) - et al.
HPLC analysis of asymmetric dimethylarginine (ADMA) and related arginine metabolites in human plasma using a novel non-endogenous internal standard
Clin. Chim. Acta
(2009) - et al.
Hyperglycemia-impaired aortic vasorelaxation mediated through arginase elevation: role of stress kinase pathways
Eur. J. Pharmacol.
(2019) - et al.
Relationship between Arginase 1 and Arginase 2 levels and genetic polymorphisms with erectile dysfunction
Nitric Oxide
(2015) - et al.
Association between arginase-containing platelet-derived microparticles and altered plasma arginine metabolism in polycystic ovary syndrome
Metabolism
(2019) - et al.
The microcirculation: a key player in obesity-associated cardiovascular disease
Cardiovasc. Res.
(2017) - et al.
Obesity
Nat. Rev. Dis. Primers
(2017) - et al.
Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal?
Cardiovasc. Res.
(2013)
Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1
Cardiovasc. Res.
Obesity-induced vascular inflammation involves elevated arginase activity
Am. J. Phys. Regul. Integr. Comp. Phys.
Association of serum arginase I with oxidative stress in a healthy population
Free Radic. Res.
Early obesity leads to increases in hepatic arginase I and related systemic changes in nitric oxide and L-arginine metabolism in mice
J. Physiol. Biochem.
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