ORIGINAL ARTICLE Circulating Levels of Vascular Endothelial Growth Factor A and Its Soluble Receptor in Patients with Biopsy-proven Nonalcoholic Fatty Liver Disease Yusuf Yilmaz, a Oya Yonal, a Ramazan Kurt, a Yesim Ozen Alahdab, a Osman Ozdogan, a Cigdem Ataizi Celikel, b Engin Ulukaya, c Nese Imeryuz, a Cem Kalayci, a and Erol Avsar a a Department of Gastroenterology, b Department of Pathology, Marmara University School of Medicine, Altunizade, Istanbul, Turkey c Department of Biochemistry, Uludag University Medical School, Gorukle, Bursa, Turkey Received for publication August 31, 2010; accepted November 29, 2010 (ARCMED-D-10-00425). Background and Aims. Vascular endothelial growth factor A (VEGF) is a multifunctional cytokine affecting angiogenesis and vascular function. The biological activity of VEGF is modulated by its soluble receptor VEGFR-1 (sVEGFR-1). We explored the associations of VEGF and sVEGFR-1 concentrations with liver histology in patients with biopsy- proven nonalcoholic fatty liver disease (NAFLD). Methods. The study was comprised of 99 patients with NAFLD and 75 healthy controls. Serum VEGF and sVEGFR-1 concentrations were measured using commercially avail- able enzyme-linked immunosorbent assays. Results. Serum VEGF levels did not differ in patients with NAFLD (1882  942 pg/mL) compared with healthy controls (1985  945 pg/mL, p 5 0.42). However, compared with healthy subjects, levels of sVEGFR-1 were significantly lower in patients with NAFLD (1.59  0.58 ng/mL vs. 1.16  0.34 ng/mL, respectively, p !0.001). After allowance for potential confounders, serum sVEGFR-1 levels retained their independent signifi- cance as a predictor of liver fibrosis in patients with NAFLD (b 5 0.19; t 5 1.81, p !0.05). Conclusions. Our results show that patients with biopsy-proven NAFLD have a signifi- cant reduction in serum sVEGFR-1 concentrations that predict the degree of liver fibrosis, independent of potential confounders. Ó 2011 IMSS. Published by Elsevier Inc. Key Words: Vascular endothelial growth factor, Nonalcoholic fatty liver disease, Liver fibrosis, Enzyme-linked immunosorbent assay, Steatohepatitis. Introduction Nonalcoholic fatty liver disease (NAFLD), a hepatic mani- festation of the metabolic syndrome (1), is the most common liver disease in developed countries and a major cause of abnormal liver function tests in hepatology prac- tice (2). The term NAFLD is used to describe a wide spec- trum of fatty liver changes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) (3). Accumulating research suggests that NAFLD is independently associated with insulin resistance (4). In addition, insulin resistance may predict the severity of liver damage or fatty infiltration in patients with NAFLD (5). These observations indicate that either insulin resistance plays a role in the pathogenesis and progression of liver damage or the two phenomena have a common pathogenic mechanism (6). Vascular endothelial growth factor A (VEGF-A) is a multifunctional cytokine originally described as a potent, secreted growth factor affecting angiogenesis and vascular function (7). VEGF is known to have numerous effects in metabolism (8,9), and altered systemic levels of this mole- cule have been reported in patients with diabetes (10,11). Interestingly, VEGF increases the survival of pancreatic islets and exerts b-cell protective effects by improving islet revascularization (8). A pilot research by Barylski et al. (12) found reduced levels of VEGF in patients with meta- bolic syndrome but this finding was not confirmed in Address reprint requests to: Yusuf Yilmaz, MD, Department of Gastro- enterology, Marmara University School of Medicine, Altunizade, Istanbul 34662, Turkey; Phone: þ90 5334403995; FAX: þ90 2166886681; E-mail: yusufyilmaz@uludag.edu.tr 0188-4409/$ - see front matter. Copyright Ó 2011 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2010.12.001 Archives of Medical Research 42 (2011) 38e43