Non-alcoholic fatty liver disease (NALFD) is considered as the hepatic manifestation of the metabolic syndrome, with insulin resistance (IR) as key underlying pathophysiological mechanism. NAFLD comprise a wide range of liver damage, from simple fatty liver to non-alcoholic steatohepatitis (NASH), including cirrhosis( 1 ). Hyperglycemia, IR and oxidative stress increase advance glycation end products (AGEs) that may contribute to the pathophysiology of NAFLD through the AGE-RAGE axis. AGEs such pentosidine, Nɛ-carboxyethyl-L-lysine (CEL) and Nɛ-carboxymethyl-L-lysine (CML) exert pathological effects by binding to AGEs receptors (RAGE), triggering inflammation, cellular dysfunction and cell death. Soluble RAGE (sRAGE) may protect by preventing AGEs/RAGE interaction( 2 ). The aim of the study was to evaluate the association of AGEs and sRAGE levels in a case (NAFLD)-control cohort with markers of liver function (ALT, AST, and GGT) and IR.
The study included 131 non-diabetic adults in age, sex and BMI matched pairs based on the presence/absence of NAFLD (liver enzymes and ultrasound hepatic steatosis)( 3 ). AGEs were analysed by liquid chromatography-mass spectrometry (CML, CEL), fluorescence (pentosidine, AGE fluorescence), colorimetry (fructosamine) and ELISA (sRAGE).
Mean values of cases were significantly different from the controls (independent t-test, *P < 0.01 selecting cases if match by age, sex and BMI). a Data are not normally distributed.
Patients’ mean age was 45 year with a BMI of 29 kg/m2. Glycation biomarkers were significantly higher in cases compared to controls, except for CML (p = 0·19). The absence of difference could be explained by the suppressed CML plasma levels observed in overweight subjects, thereby reducing our ability to detect an effect( 4 ). Compared to controls, AGEs were 36 % higher in cirrhosis patients, 18 % higher in NASH and 27 % higher in fatty liver patients (p < 0·01). Two-fold lower sRAGE levels were present in cases and were inversely associated with CEL and AGE fluorescence (r = 0·59, p < 0·01). sRAGE levels were inversely associated with the severity of NAFLD based on liver function and IR (r = 0·44, p < 0·01), and the stage of the disease (r = 0·38, P < 0·001). These findings support the hypothesis that AGEs-RAGE axis is associated with the reduction of hepatic function and highlight their potential as markers of NAFLD progression.
The cross-sectional study was financially supported by the Hellenic Foundation of Gastroenterology & Nutrition. S.P acknowledges receipt of a CONACyT Ph.D. scholarship.