Correlation between LRG1 and Adipokines in Psoriasis

Background and Objective . Patients with psoriasis may exhibit abnormal changes in serum adipokine levels, which are often related to disease severity of the disease. Leucine-rich alpha-2-glycoprotein 1 (LRG1) is an acute-phase infammatory protein that may be linked to adipokines in psoriasis. In this study, we evaluated the diferences in the expression of adipokines and LRG1 between patients with psoriasis and healthy individuals, analyzed the correlation between the expression of LRG1 and adipokines, and explored their relationship with psoriatic lesions. Methods . In this cross-sectional study, patients with psoriasis ( n � 54) and healthy controls ( n � 26) were enrolled, and their clinical characteristics were recorded. Fasting venous blood samples were collected from each participant. Te serum concentrations of leptin, resistin, adiponectin, and LRG1 in each sample were measured using the enzyme-linked immunosorbent assay. Results . Te study included 54 patients with psoriasis vulgaris and 26 healthy controls. Te serum levels of LRG1, leptin, and resistin were signifcantly higher in patients with psoriasis than in healthy controls. Conversely, adiponectin levels were signifcantly lower in patients with psoriasis. Te study showed that LRG1 expression was positively correlated with leptin and resistin expression but negatively correlated with adiponectin expression. Interestingly, only leptin, resistin, and LRG1 expression showed a linear correlation with the Psoriasis Area and Severity Index (PASI). When we categorized patients with psoriasis based on their LRG1 levels, we observed that the group with high LRG1 levels showed a higher PASI. Conclusions . We observed a signifcant correlation between LRG1 and adipokine expression in patients with psoriasis. In addition, the expression levels of LRG1, leptin, and resistin were observed to be correlated with the severity of psoriasis. We believe that the occurrence and development of psoriasis are collectively infuenced by LRG1 and leptin/resistin expression.


Introduction
Psoriasis is a chronic skin disease that afects over 60 million people worldwide.Its overall prevalence ranges from 0.1% in East Asia to 1.5% in Western Europe [1].Te occurrence and development of psoriasis are driven by T cell dysfunction and a complex imbalance in the network of infammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-23 (IL-23), and the IL-17 family [2].Findings from several studies have demonstrated the involvement of adipokines, including leptin, resistin, and adiponectin, in the pathogenesis of psoriasis.Elevated levels of leptin and resistin, as well as decreased levels of adiponectin, have been observed in patients with psoriasis, which may contribute to the severity of skin lesions [3].Chronic subclinical low-grade infammation could result from the abnormal secretion of adipokines and cytokines in the skin and adipose tissue.Tis infammation could contribute to the stimulation, diferentiation, and proliferation of keratinocytes and immune cells [4].Leucine-rich α-2 glycoprotein 1 (LRG1) is an acutephase infammatory protein that has been linked to cancer, infection, and autoimmune diseases [5,6].Studies have shown that patients with psoriasis have signifcantly higher serum levels of LRG1, and LRG1 could be a valuable biomarker for monitoring disease activity and treatment efcacy [7,8].Furthermore, the sensitivity of LRG1 as a biomarker is considerably higher than that of C-reactive protein [8].LRG1 is synthesized primarily by the liver and neutrophils and is involved in various biological processes such as infammation, lipid metabolism, and glucose metabolism [9].However, the correlation between LRG1 and adipokine expression in patients with psoriasis remains unclear.
In this study, we investigate the association between the aberrant expression of adipokines and LRG1 in patients with psoriasis as well as their relationship with disease severity.

Selection of Patients.
Tis study was a two-center observational cross-sectional investigation that included patients with psoriasis who visited the Department of Dermatology of Dongzhimen Hospital and the Air Force Medical Center of PLA from December 2022 to February 2023.Te inclusion criteria were patients with psoriasis vulgaris who were 18 to 64 years old.Participants were required to refrain from using systemic antipsoriasis drugs for at least 1 month before the study.In addition, all participants were informed and agreed to blood sampling.Te exclusion criteria included pustular psoriasis, other types of psoriasis, coinfection, tumor, other autoimmune diseases, severe cardiovascular disease, and blood system disease.In addition, 26 healthy controls were recruited as baseline controls for each serological index.Participants were informed and agreed to blood sampling.Tis study was approved by the Dongzhimen Hospital and Air Force Medical Center of PLA Ethics Committee (Registration Number: 2022DZMEC-287-02).

Clinical and Serological
Variables.Te basic clinical data included were gender, age, BMI, disease duration, and PASI score at the time of enrollment.BMI was calculated by dividing the body weight of each patient in kilograms by the square of their height in centimeters.Te levels of the biochemical indicators were measured by collecting venous blood from each participant on an empty stomach.Te blood sample was then centrifuged at 2500 rpm for 20 min to collect the serum, which was stored in a −80 °C freezer for future use.

Statistical Analysis.
Descriptive statistical analysis was performed on all variables using IBM SPSS Statistics 24.0 and Microsoft Excel 2016.For continuous variables that conformed to a normal distribution, the mean ± standard deviation was used to express data, and the diference between groups was expressed using an unpaired t-test.Variables that did not adhere to a normal distribution were expressed using the median (25th percentile and 75th percentile) values.We used nonparametric rank-sum tests to compare groups.Dichotomous variables were expressed as percentages, and we used chi-square tests to compare groups.We conducted linear regression analyses among variables and drew graphs using GraphPad Prism 8. Statistical signifcance was set at P value <0.05.

Results
Te study included 54 patients with psoriasis vulgaris and 26 healthy controls.Eighty serum samples were collected from the participants.Te results showed signifcant diferences in age and BMI between the two groups.Patients with psoriasis were younger but had higher BMI values than healthy controls.We observed notable variations in the serum levels of leptin, resistin, adiponectin, and LRG1 in the two groups.Specifcally, patients with psoriasis had signifcantly higher levels of leptin, resistin, and LRG1 than healthy controls (P < 0.001).Conversely, the levels of adiponectin were lower in patients with psoriasis than in healthy controls (P < 0.001) (Figure 1).To minimize the impact of age and BMI variations on adipokine and LRG1 expression, we conducted a 1 :1 matching based on age and BMI in the groups.Despite this, the results indicated signifcant diferences between the groups (P ≤ 0.001).Basic clinical data and serological indicator diferences are shown in Table 1.
Linear regression was used to examine the association between the expression patterns of LRG1 and leptin, resistin, or adiponectin.Simultaneously, we analyzed the correlation of these expression patterns with the PASI.Results indicated a signifcant linear correlation between PASI and LRG1 (F � 6.17, P � 0.0163), leptin (F � 5.511, P � 0.0227), and resistin expression (F � 6.054, P � 0.0172) but showed no correlation with adiponectin (P � 0.1045) (Figure 2).Tere was a signifcant positive correlation between LRG1 and leptin (F � 3643, P < 0.0001) and resistin (F � 2647, P < 0.0001), while a negative correlation was found between LRG1 and adiponectin (F � 96.01, P < 0.0001) (Figure 3).Meanwhile, a linear correlation was also observed between LRG1 and leptin (F � 253.5, P < 0.0001) and resistin (F � 12.50, P � 0.0017) expression in healthy controls.However, this correlation was weaker compared to that in patients with psoriasis.In addition, the association of LRG1 expression with adiponectin expression was not observed in healthy participants.To further investigate the correlation between LRG1 expression and psoriasis, we categorized patients based on their serum levels of LRG1.Patients with higher serum levels of LRG1 (≥15 ng/mL) had a signifcantly higher PASI score than patients with lower levels of LRG1 (P < 0.05).Although patients with lower levels of LRG1 appeared to have had psoriasis for a longer duration, no statistically signifcant diference was observed between the groups (P > 0.05) (Figure 4).

Discussion
Psoriasis is a chronic skin disease caused by the abnormal proliferation of keratinocytes and the release of proinfammatory cytokines [10].Recent studies have revealed that adipokines contribute signifcantly to the pathological progression of psoriasis [11].Adipokines are a group of biologically active proteins primarily produced by adipocytes.
Tere are various types of adipokines, including leptin, resistin, adiponectin, visfatin, and chemerin [12].Adipokines play a signifcant role in various cellular signal transductions during metabolic processes, and they also exert a signifcant impact on immune infammation regulation [11,13].Our research fndings indicated that, compared to healthy individuals, patients with psoriasis showed signifcantly abnormal levels of leptin, resistin, and adiponectin.Tese abnormal levels persisted even after controlling for age and BMI and were closely correlated with the severity of skin lesions.Te relationship may be attributed to an abnormal increase in the levels of proinfammatory adipokines, such as leptin and resistin, and a decrease in the levels of antiinfammatory adipokines, such as adiponectin [12].Leptin is primarily produced by adipocytes in white fat and plays a crucial role in regulating the body's energy balance.Its levels are often elevated in patients with psoriasis and obesity and are closely associated with BMI [14].In psoriasis, leptin has been shown to exert a stimulating efect on angiogenesis and the production of infammatory factors such as IL-6, TNF-α, IL-8, and IL-17 [15,16].Under normal conditions, leptin is only detected in the basal layer of the skin.However, in individuals with psoriasis, it can be overexpressed in all layers of the epidermis, particularly in Figure 1: Te serum levels of leptin and resistin in patients with psoriasis were signifcantly higher than in healthy controls (P < 0.001), whereas adiponectin levels were lower (P < 0.001) (a).Additionally, the serum levels of LRG1 were signifcantly higher in patients with psoriasis (P < 0.001) (b).  4 Dermatologic Terapy infammatory cells [17].Research has indicated that leptin can aggravate the infammatory response of keratinocytes, a process that is mediated by TNF-α and IL-17A.Tis can lead to the worsening of psoriatic lesions [18].Resistin, like leptin, is closely associated with an individual's BMI and can promote infammation by activating the nuclear factor kappa-B (NF-κB) signaling pathway in human macrophages and peripheral monocytes.Tis leads to the production of proinfammatory cytokines such as IL-6, IL-12, and TNF-α [19].A positive correlation exists between the elevation of resistin levels and the severity of psoriasis, suggesting that resistin may play a role in the pathogenesis of psoriasis [20].Adiponectin exhibits antiinfammatory efects, and its secretion levels are signifcantly low in patients with psoriasis [21].It inhibits the expression of NF-κB and retinoid-related orphan receptor-ct (ROR-ct) while upregulating IL-10 secretion, which also inhibits the diferentiation of T17 cells and regulates toll-like receptors (TLRs).In response to this, TLRs exhibit antiinfammatory efects [15].
Our fndings indicate a strong positive linear correlation between leptin and resistin expression and PASI.However, we did not observe a signifcant linear relationship between PASI and adiponectin expression, which may be attributed to sample size and other factors.Tese results provide sufcient evidence to support the strong association between adipokine expression and psoriasis.LRG1 is a member of a highly conserved protein family that contains leucine-rich repeat domains.It is primarily synthesized by the liver and neutrophils and can be rapidly secreted in response to infection or infammatory stimulation [5].Increased levels and the ectopic expression of LRG1 are typically associated with disease pathology [5,6].In a recent study, the use of bio-orthogonal noncanonical amino-acid tagging (BONCAT) and mass spectrometry facilitated the characterization of LRG1 as a novel adipokine [22].Another study showed that LRG1 mRNA and protein levels were signifcantly higher in adipose tissue than in liver tissue [9].LRG1 has been shown to exert a benefcial impact on the survival and function of adipocytes.Tis can be attributed to its ability to inhibit adipocyte apoptosis through the RAS oncogene family member (RAB31) protein [23].Currently, limited research is available on the connection between LRG1 and other adipokines.However, our fndings revealed that LRG1 expression exhibited a signifcant positive linear correlation with leptin and resistin expression but a strong negative linear correlation with adiponectin expression.Tis suggested a close relationship between the expression of LRG1 and these three adipokines.Currently, LRG1 is being used as a marker to measure disease activity in rheumatoid arthritis and infammatory bowel disease.Some researchers have suggested that it may also be useful in assessing and treating patients with psoriasis [8].In our study, we found a positive correlation between LRG1 expression and PASI.Patients with higher serum LRG1 levels (≥15 ng/mL) also had a more active form of psoriasis and severe skin lesions (P < 0.05) compared to individuals with lower serum levels of LRG1.However, patients with lower serum levels of LRG1 tended to have a longer disease duration, although the diference in this parameter between the two groups was not statistically signifcant (P > 0.05).Tis may be because LRG1, as an acute-phase infammatory protein, induces the production of infammatory factors such as transforming growth factorβ (TGF-β), IL-1β, TNF-α, and IL-6.As a result, liver cells synthesize more LRG1, thus participating in a feedback mechanism that exacerbates psoriatic lesions and infammation in the skin [7].Another research has demonstrated that LRG1 plays a crucial role in enhancing the migration of keratinocytes and expediting the healing of skin injuries.Tis fnding holds signifcant implications for the restoration of the skin barrier [24].In conclusion, our fndings suggest that LRG1 may work in conjunction with leptin/resistin to enhance the impact of psoriatic infammatory factors.Tis mechanism highlights the potential role of adipokines in the pathogenesis of psoriasis.
Te limitations of this study include its cross-sectional design, which only allowed for the analysis of correlations between variables and not causal relationships.In addition, the sample size may restrict the generalizability of our fndings, and future studies with larger sample sizes are necessary to confrm our results.Further research is necessary to fully understand the mechanism of action and potential applications of LRG1 in treating psoriasis.

Conclusion
Tis study provides valuable insights into the relationship between psoriasis and adipokine expression.Patients with psoriasis often have higher levels of LRG1, leptin, and resistin as well as lower levels of adiponectin than healthy controls.Te elevation of LRG1 levels was found to be closely associated with the development of psoriatic skin lesions and the expression of other adipokines, suggesting that LRG1 may work in conjunction with leptin/resistin to exacerbate psoriatic infammation.Tis study is among the frst to investigate the relationship between the expression of LRG1 and adipokines in individuals with psoriasis.

Table 1 :
Clinical characteristics of patients with psoriasis and healthy controls.