THE ROLE OF SELECTINS IN THE FORMATION AND DEVELOPMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE

ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-12 1158 THE ROLE OF SELECTINS IN THE FORMATION AND DEVELOPMENT OF NONALCOHOLIC FATTY LIVER DISEASE Ro‘zimova Gulhayo Bayramovna 1st year master’s student in internal diseases,Urgench state medical institute, Urgench, Uzbekistan Abstract. Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing global health problem and represents the hepatic manifestation of metabolic syndrome. The pathogenesis of NAFLD is complex and involves insulin resistance, lipid accumulation, oxidative stress, chronic inflammation, and endothelial dysfunction. Selectins, a family of cell adhesion molecules, play a crucial role in leukocyte–endothelium interactions and inflammatory cell recruitment. Increasing evidence suggests that selectins contribute to endothelial activation and inflammatory processes in metabolic disorders, including NAFLD. This study aimed to investigate the role of P-, E-, and L-selectins in the formation and progression of NAFLD. The findings demonstrate that altered circulating levels of selectins are closely associated with the severity of hepatic steatosis and inflammatory activity, highlighting their potential as biomarkers and therapeutic targets in NAFLD. Key words: non-alcoholic fatty liver disease, selectins, endothelial dysfunction, inflammation, adhesion molecules, metabolic syndrome. Introduction. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and affects approximately 25–30% of the adult population. It encompasses a wide spectrum of liver pathology, ranging from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), progressive fibrosis, cirrhosis, and hepatocellular carcinoma [1]. NAFLD is strongly associated with obesity, type 2 diabetes mellitus, dyslipidemia, arterial hypertension, and insulin resistance, and is increasingly recognized as a multisystem disease with significant cardiovascular implications [2]. The pathogenesis of NAFLD is multifactorial and is currently explained by the “multiple-hit” hypothesis, which includes genetic predisposition, altered lipid metabolism, mitochondrial dysfunction, oxidative stress, gut microbiota alterations, and chronic low-grade inflammation [3]. Among these mechanisms, endothelial dysfunction has emerged as a key contributor to disease progression, linking metabolic disturbances to hepatic inflammation and fibrosis [4]. Endothelial dysfunction is characterized by impaired nitric oxide bioavailability, increased oxidative stress, and enhanced expression of adhesion molecules on endothelial cells. These changes promote leukocyte adhesion, migration, and infiltration into hepatic tissue, thereby amplifying inflammatory responses and hepatocellular injury [5]. Selectins represent a family of calcium-dependent adhesion molecules belonging to the C-type lectin family. The selectin family consists of three members: E-selectin (endothelial selectin), P-selectin (platelet and endothelial selectin), and L-selectin (leukocyte selectin). These molecules play a pivotal role in the initial steps of leukocyte recruitment, particularly leukocyte rolling along the activated endothelium during inflammatory responses [6]. E-selectin is expressed exclusively on activated endothelial cells in response to pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). P-selectin is rapidly translocated to the cell surface from intracellular storage granules in endothelial cells and platelets, ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-12 1159 while L-selectin is constitutively expressed on leukocytes and regulates their homing and migration [7]. Accumulating evidence suggests that dysregulation of selectin expression is involved in metabolic and inflammatory diseases, including atherosclerosis, diabetes mellitus, and NAFLD [8]. However, the clinical relevance of selectins in NAFLD progression remains insufficiently explored, particularly in Central Asian populations. Aim of the study. The aim of this study was to evaluate the role of P-, E-, and L-selectins in the formation and progression of non-alcoholic fatty liver disease and to analyze their association with biochemical parameters, inflammatory activity, and disease severity. Materials and methods. This cross-sectional observational study was conducted at the Khorezm multidisciplinary medical center. A total of 120 patients aged 18 to 65 years with confirmed NAFLD were enrolled between 2023 and 2024. NAFLD was diagnosed based on clinical data, biochemical markers, and abdominal ultrasonography. Patients with significant alcohol consumption (>20 g/day for women and >30 g/day for men), viral hepatitis (HBV, HCV), autoimmune liver diseases, hereditary liver disorders, malignant neoplasms, or use of hepatotoxic medications were excluded from the study. A control group of 40 ageand sex-matched healthy individuals without metabolic disorders or liver disease was included for comparative analysis. All participants underwent comprehensive clinical evaluation, anthropometric measurements, and laboratory testing. Biochemical parameters included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting glucose, and insulin levels. Serum concentrations of soluble P-selectin, E-selectin, and L-selectin were measured using enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions. Statistical analysis was performed using standard statistical software. Quantitative data were expressed as mean ± standard deviation. Pearson correlation analysis was used to evaluate associations between selectin levels and clinical or biochemical parameters. Differences were considered statistically significant at p<0.05. Results. Patients with NAFLD demonstrated significantly higher serum levels of soluble Eselectin and P-selectin compared to the control group (p<0.05). The elevation of E-selectin was most pronounced in patients with moderate to severe hepatic steatosis, suggesting active endothelial involvement in disease progression. A positive correlation was observed between E-selectin levels and ALT activity (r=0.43, p<0.01), as well as with serum triglyceride levels and body mass index. Pselectin levels were also positively associated with markers of insulin resistance and systemic inflammation. In contrast, L-selectin levels were significantly lower in patients with advanced metabolic disturbances and higher grades of steatosis. This decrease may reflect chronic immune activation and impaired leukocyte trafficking in progressive NAFLD. These findings indicate a distinct imbalance in selectin expression, reflecting endothelial activation, platelet involvement, and immune dysregulation in NAFLD. Discussion. The results of this study support the concept that selectins play a significant role in the pathogenesis of NAFLD. Elevated levels of E-selectin reflect endothelial activation and inflammation, which are central mechanisms linking metabolic disorders to hepatic injury. Increased P-selectin levels suggest platelet activation and vascular involvement, which may contribute to microcirculatory disturbances in the liver. ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-12 1160 The observed reduction in L-selectin levels in advanced NAFLD may be associated with chronic inflammatory exhaustion or altered leukocyte migration patterns. Similar findings have been reported in other chronic inflammatory and metabolic conditions [9]. The involvement of selectins in NAFLD underscores the close relationship between liver pathology and systemic vascular dysfunction. These molecules may serve not only as biomarkers of disease severity but also as potential therapeutic targets aimed at modulating inflammatory cell recruitment. Conclusions. Selectins play a crucial role in the formation and progression of non-alcoholic fatty liver disease through mechanisms of endothelial activation and inflammation. Elevated serum levels of E-selectin and P-selectin are associated with increased disease severity, hepatic steatosis, and biochemical markers of liver injury. Reduced L-selectin levels may indicate immune dysregulation in advanced stages of NAFLD. Selectins represent promising biomarkers for assessing disease activity and potential targets for therapeutic intervention in NAFLD. References: 1. Younossi Z.M., et al. Global epidemiology of nonalcoholic fatty liver disease. Hepatology. 2016;64(1):73–84. 2.Byrne C.D., Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1):S47–S64. 3.Tilg H., Moschen A.R. Evolution of inflammation in nonalcoholic fatty liver disease. Gastroenterology.2010;139(6):1802–1805. 4. Sookoian S., Pirola C.J. Endothelial dysfunction and NAFLD. Clin Sci. 2017;131(7):639–652. 5. Targher G., et al. NAFLD and vascular disease. Atherosclerosis. 2018;273:175–180. 6. Kansas G.S. Selectins and their ligands. Blood. 1996;88(9):3259–3287. 7. Ley K., et al. The leukocyte adhesion cascade. Nat Rev Immunol. 2007;7(9):678–689. 8. Simons N., et al. Soluble E-selectin and NAFLD. Liver International. 2020;40(5):1079–1088. 9. Koroy P.V., et al. Selectins in metabolic liver disease. Therapy. 2021.