Association of Serum Zinc-a2-Glycoprotein with Non-Alcoholic Fatty Liver Disease
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver condition globally. It is closely associated with visceral obesity and is often regarded as the hepatic manifestation of metabolic syndrome, with insulin resistance playing a pivotal role in its development. Despite the established link between NAFLD and metabolic syndrome, the precise pathogenesis of NAFLD remains elusive. Recent research, including studies from our group and others, has highlighted the potential role of zinc-a2-glycoprotein (ZAG), also known as alpha-2-glycoprotein 1, zinc-binding, in the context of obesity and related metabolic disorders. ZAG, a novel adipokine, has been proposed as a key regulator of lipid metabolism and insulin sensitivity. However, the clinical significance of ZAG in NAFLD has not been thoroughly explored. To address this gap, we conducted a case-control study to measure serum ZAG levels and investigate their association with various metabolic parameters in patients with NAFLD.
The study involved 308 Chinese individuals, comprising 168 patients diagnosed with NAFLD (aged 25–64 years; 89 males and 79 females) and 140 healthy controls (aged 22–66 years; 79 males and 61 females). Participants were recruited following routine physical examinations. All subjects completed a standardized questionnaire that captured demographic information, medical history, recent medication use, and lifestyle factors such as smoking and alcohol consumption. NAFLD was diagnosed using ultrasonic imaging, and the severity of the condition was categorized into three grades based on the degree of hepatic steatosis. Controls were defined as individuals without metabolic syndrome or hepatic steatosis.
Anthropometric measurements, including height, weight, waist circumference, and blood pressure, were taken using standardized protocols. Body fat percentage (Fat %) was assessed using bioelectrical impedance analysis. Additionally, lipid profiles, glucose levels, and insulin concentrations were measured using established methods. Serum ZAG concentrations were quantified using commercially available human ZAG enzyme-linked immunosorbent assay kits (Biovendor, Modrice, Czech Republic) in accordance with the manufacturer’s instructions. The study received approval from the Human Research Ethics Committee of the hospital and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. Data analysis was performed using SPSS version 17.0 (Chicago, IL, USA).
Our findings revealed that serum ZAG levels were significantly lower in patients with NAFLD compared to healthy controls (41.21 ± 8.21 mg/L vs. 51.32 ± 9.87 mg/L, P < 0.001). Furthermore, a decreasing trend in serum ZAG levels was observed with increasing severity of hepatic steatosis as assessed by ultrasonography (P for linear trend < 0.001). This observation aligns with previous studies that reported reduced ZAG expression in palmitic acid-treated hepatocytes, liver tissue of NAFLD patients, and obese mice. These studies suggested that ZAG overexpression could mitigate NAFLD by reducing hepatic steatosis, insulin resistance, and inflammation. Based on these findings, we hypothesize that ZAG may act as a protective factor in the pathogenesis of NAFLD. However, the cross-sectional design of our study limits our ability to establish a causal relationship between serum ZAG levels and NAFLD. Future longitudinal studies are needed to explore this relationship further.
It is noteworthy that our results differ from those reported by Yilmaz et al., who found no significant difference in serum ZAG concentrations between NAFLD patients and healthy controls. This discrepancy may be attributed to differences in ethnicity, adiposity levels, or the severity of NAFLD among study populations. Additionally, adiposity or metabolic disorders could potentially induce resistance to ZAG actions, such as insulin or leptin resistance, leading to increased secretion and release of ZAG.
Next, we examined the relationship between serum ZAG levels and various anthropometric and biochemical parameters in all participants. Our analysis revealed significant negative associations between serum ZAG levels and blood pressure, lipid profiles (elevated total cholesterol and triglycerides, reduced high-density lipoprotein cholesterol), glucose metabolic parameters (fasting blood glucose and fasting insulin), insulin resistance indices (homeostasis model assessment of insulin resistance, HOMA-IR), and obesity-related parameters such as body mass index, waist circumference, and Fat % (P < 0.05). To identify independent predictors of serum ZAG levels, we performed multiple linear regression analysis, which included triglyceride levels, waist circumference, and HOMA-IR. These parameters were found to be independently associated with serum ZAG levels (P < 0.01). These findings suggest that reduced ZAG levels may contribute to the development of NAFLD through pathways involving obesity and insulin resistance. However, the involvement of other unidentified factors cannot be ruled out.
Moreover, serum ZAG concentrations remained strongly associated with NAFLD even after adjusting for age, gender, body mass index, lipid profile, and glucose metabolic parameters in a multivariate logistic regression model (OR = 0.824, 95% confidence interval = 0.722–0.941, P = 0.009). To further explore this relationship, we categorized participants into four groups based on serum ZAG levels and analyzed the prevalence of NAFLD across these groups. A significant linear trend was observed, with decreasing ZAG levels being independently associated with an increased risk of NAFLD (P = 0.004). Specifically, the risk of NAFLD was 24.67% higher in the group with the lowest serum ZAG levels (quartile 1) compared to the group with the highest levels (quartile 4).
In summary, our study demonstrates that serum ZAG levels are negatively associated with the prevalence of NAFLD and various obesity-related metabolic parameters. These findings suggest that ZAG may serve as a novel protective factor in the development of NAFLD, potentially through mechanisms involving obesity and insulin resistance. Further research is needed to elucidate the underlying pathways and establish the causal relationship between ZAG and NAFLD.
doi.org/10.1097/CM9.0000000000000873
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