Insight into the negative effect and lipid profile alterations in liver of mice exposed to methylimidazolium ionic liquids, a novel "green" solvent.

Background: Ionic liquids (ILs) have been recognized as potential environmentally friendly solvents; however, their potential toxicity to living organisms warrants thorough investigation, particularly for novel-generation ILs in mammalian models. Methods: In this study, we examined the hepatic effects and disruption of lipid metabolism in mice exposed to 1-heptyl-3-methylimidazolium chloride (C7[MIM]Cl), a novel ILs. After four weeks of oral administration at different dosages (2.38, 5.95, and 11.9 mg/kg b.w.), we conducted clinical chemistry analysis and histopathological examination of the liver to assess biochemical and structural changes. Results: The low-dose C7[MIM]Cl group exhibited a significant increase in alanine aminotransferase (ALT) levels, while aspartate aminotransferase (AST) levels were elevated in both low-dose and high-dose groups without statistical significance. Histopathological examination showed inflammatory cell infiltration and red blood cell aggregation in the livers of mice exposed to C7[MIM]Cl, particularly in the high-dose group. Oxidative stress levels showed moderate changes in response to C7[MIM]Cl exposure. Notably, hepatic biochemical parameters revealed a dose-dependent increase in triglycerides (TG) levels with statistically significant differences compared to the control group (P ≤ 0.01). Targeted lipidomic analysis revealed notable alterations in liver lipids of mice exposed to C7[MIM]Cl, with lysophosphatidylethanolamine (18:0), phosphatidylcholines (18:0), and phosphatidylcholines (19:0) identified as critical lipids associated with C7[MIM]Cl exposure. Furthermore, metabolic pathway analyses demonstrated significant disturbances in the glycerophospholipid metabolic pathway. Conclusion: These findings provide valuable insights into the hepatic effects of C7[MIM]Cl exposure and novel perspectives on the disruption of lipid metabolism underlying ILs toxicity.

Acylation-stimulating protein (ASP)/complement C3adesArg deficiency results in increased energy expenditure in mice.

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(-/-) ASP-deficient mice had elevated oxygen consumption (VO2) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 +/- 2.4 m whereas KO mice moved 30.1 +/- 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT -68%, WAT -29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice.

Acylation-stimulating protein precursor proteins in adipose tissue in human obesity.

Recent reports have suggested a link between acylation-stimulating protein (ASP) and complement C3 with obesity, insulin resistance, coronary artery disease, and hyperlipidemia. Our aim was to examine the mRNA expression of C3 and other factors related to ASP production (such as factor B and adipsin) in adipose tissue. The influence of gender and obesity was examined in subcutaneous (SC) and omental (OM) tissues from 16 males and 16 females with body mass index (BMI) from 20 to 54 kg/m(2). The results demonstrate that factor B mRNA expression is higher in males than females in both SC and OM tissues. In female SC tissue, C3 and adipsin mRNA decrease with increasing BMI (r = 0.557, P =.025 and r = 0.717 P =.002, respectively), with no change in factor B. By contrast, in males there was a pronounced increase in C3, adipsin, and factor B in OM tissue with increasing BMI (r = 0.759 P =.001, r = 0.650 P =.006, and r = 0.568 P =.022, respectively). Of note, however, in both men and women there was a marked increase in the OM/SC ratio of C3 and adipsin with increasing BMI. These results suggest that in female SC adipose tissue, there is downregulation of factors related to ASP production in obesity, perhaps to limit further expansion of adipose tissue. In males, there is increased expression in OM tissue. In addition, relative OM/SC expression increases with obesity and these changes may contribute to the development of visceral adipose tissue.

Critical review of acylation-stimulating protein physiology in humans and rodents.

In the last few years, there has been increasing interest in the physiological role of acylation-stimulating protein (ASP). Recent studies in rats and mice, in particular in C3 (-/-) mice that are ASP deficient, have advanced our understanding of the role of ASP. Of note, the background strain of the mice influences the phenotype of delayed postprandial triglyceride clearance in ASP-deficient mice. Administration of ASP in all types of lean and obese mice studied to date, however, enhances postprandial triglyceride clearance. On the other hand, regardless of the background strain, ASP-deficient mice demonstrate reduced body weight, reduced leptin and reduced adipose tissue mass, suggesting that ASP deficiency results in protection against development of obesity. In humans, a number of studies have examined the relationship between ASP, obesity, diabetes and dyslipidemia as well as the influence of diet, exercise and pharmacological therapy. While many of these studies have small subject numbers, interesting observations may help us to better understand the parameters that may influence ASP production and ASP action. The aim of the present review is to provide a comprehensive overview of the recent literature on ASP, with particular emphasis on those studies carried out in rodents and humans.

Acylation-stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice.

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. ASP administration results in more rapid postprandial lipid clearance. In mice, C3 (the precursor to ASP) knockout results in ASP deficiency and leads to reduced body fat and leptin levels. The protective potential of ASP deficiency against obesity and involvement of the leptin pathway were examined in ob/ob C3(-/-) double knockout mice (2KO). Compared with age-matched ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance; associated with decreased body weight (4-17 weeks age: male: -13.7%, female: -20.6%, p < 0.0001) and HOMA (homeostasis model assessment) index (-37.7%), suggesting increased insulin sensitivity. By contrast, food intake in 2KO mice was +9.1% higher over ob/ob mice (p < 0.001, 2KO 5.1 +/- 0.2 g/day, ob/ob 4.5 +/- 0.2 g/day, wild type 2.6 +/- 0.1 g/day). The hyperphagia/leanness was balanced by a 28.5% increase in energy expenditure (oxygen consumption: 2KO, 131 +/- 8.9 ml/h; ob/ob, 102 +/- 4.5 ml/h; p < 0.01; wild type, 144 +/- 8.9 ml/h). These results suggest that the ASP regulation of energy storage may influence energy expenditure and dynamic metabolic balance.