Adiponectin Receptor Agonist AdipoRon Relieves Endotoxin-Induced Acute Hepatitis in Mice
Adiponectin, a key adipokine, plays a pivotal role in maintaining energy homeostasis and regulating inflammation. Despite its beneficial effects, the short half-life of adiponectin limits its therapeutic potential. Recently, AdipoRon, a small-molecule adiponectin receptor agonist with a longer half-life, has been synthesized. This study explores the potential therapeutic effects of AdipoRon in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis, a widely used inflammatory model.
Introduction
Adipose tissue is not only a storage site for energy but also secretes various adipokines with extensive regulatory activities. Among these, adiponectin is the most abundant and plays critical roles in energy homeostasis and inflammation regulation. Adiponectin enhances insulin sensitivity by suppressing gluconeogenesis, making it a promising target for diabetes treatment. Beyond metabolic regulation, adiponectin also exhibits anti-inflammatory properties, as evidenced by its ability to suppress pro-inflammatory cytokines and alleviate inflammatory injuries in various disease models.
However, the short half-life of adiponectin restricts its clinical application. To address this, AdipoRon, a small-molecule adiponectin receptor agonist, was developed. AdipoRon mimics the beneficial effects of adiponectin in diabetes and atherosclerosis and has shown anti-inflammatory effects in animal models of spinal cord injury. This study investigates the effects of AdipoRon on LPS/D-Gal-induced acute hepatitis, focusing on inflammatory response, hepatocyte apoptosis, liver injury, and animal survival.
Materials and Methods
Male BALB/c mice, aged 6 to 8 weeks, were used in this study. The mice were divided into three sets. In set 1, 32 mice were randomized into four groups: control, AdipoRon, LPS/D-Gal, and AdipoRon + LPS/D-Gal. Plasma samples were collected for tumor necrosis factor-alpha (TNF-α) detection. In set 2, 32 mice were similarly divided and sacrificed 6 hours post-LPS/D-Gal injection for plasma and liver tissue collection. In set 3, 80 mice were used for survival observation, with survival rates, plasma aminotransferases, and histopathological damage assessed.
LPS and D-Gal were administered intraperitoneally at concentrations of 0.01 mg/kg and 700 mg/kg, respectively. AdipoRon was administered at 100 mg/kg 30 minutes before LPS/D-Gal injection. Plasma aminotransferases (ALT and AST) were measured using test kits, and TNF-α levels were detected via ELISA. Caspase activities were assessed using colorimetric assay kits, and cleaved caspase-3 expression was determined via Western blotting. Hepatocyte apoptosis was evaluated using the TUNEL assay.
Results
AdipoRon significantly attenuated LPS/D-Gal-induced liver injury and improved survival rates. The survival rate of AdipoRon-treated mice was 60% at 72 hours, compared to 10% in untreated mice. Histopathological analysis revealed that AdipoRon alleviated liver tissue damage induced by LPS/D-Gal. Plasma ALT and AST levels, which were markedly elevated in LPS/D-Gal-treated mice (2106.3 ± 781.9 U/L and 566.5 ± 243.4 U/L, respectively), were significantly reduced by AdipoRon (286.8 ± 133.1 U/L and 180.1 ± 153.3 U/L, respectively).
AdipoRon also suppressed LPS/D-Gal-induced TNF-α production. TNF-α levels in the LPS/D-Gal group were 328.6 ± 121.2 pg/mL, compared to 213.4 ± 52.2 pg/mL in the AdipoRon + LPS/D-Gal group. Furthermore, AdipoRon inhibited hepatocyte apoptosis, as evidenced by a reduction in TUNEL-positive cells. Caspase-3, caspase-8, and caspase-9 activities, which were elevated in LPS/D-Gal-treated mice (2.04-fold, 2.03-fold, and 2.14-fold of control, respectively), were reduced by AdipoRon (1.34-fold, 1.31-fold, and 1.43-fold of control, respectively). Western blotting confirmed that AdipoRon down-regulated cleaved caspase-3 expression (0.28-fold of the LPS/D-Gal group).
Discussion
The findings of this study demonstrate that AdipoRon effectively attenuates LPS/D-Gal-induced acute hepatitis by suppressing inflammatory responses and hepatocyte apoptosis. AdipoRon reduced plasma TNF-α levels, inhibited caspase activation, and decreased hepatocyte apoptosis, leading to improved liver histopathology and increased survival rates. These results suggest that AdipoRon has potential therapeutic value for acute hepatitis.
Adiponectin’s anti-inflammatory and anti-apoptotic properties are well-documented. In this study, AdipoRon’s ability to suppress TNF-α production aligns with previous findings that adiponectin inhibits pro-inflammatory signaling in various cell types. Additionally, AdipoRon’s inhibition of caspase activation and reduction in TUNEL-positive cells highlight its anti-apoptotic effects, which are consistent with its protective roles in other disease models.
The hepatoprotective effects of AdipoRon may be mediated through adiponectin receptor signaling, although the exact molecular mechanisms remain to be fully elucidated. The correlation between adiponectin levels and hepatic disorders further underscores the potential of AdipoRon as a therapeutic agent for liver diseases. However, future studies are needed to confirm whether AdipoRon’s effects are specifically mediated by adiponectin receptors and to explore the downstream signaling pathways involved.
Conclusion
This study demonstrates that AdipoRon effectively alleviates LPS/D-Gal-induced acute hepatitis by reducing inflammatory responses and hepatocyte apoptosis, resulting in improved liver histopathology and increased survival rates. These findings suggest that AdipoRon could be a promising therapeutic agent for acute hepatitis, warranting further investigation into its mechanisms of action and potential clinical applications.
doi.org/10.1097/CM9.0000000000000488
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