Abstract 18947: Circulating esRAGE is Associated with a Pro-Inflammatory/Pro-Atherothrombotic Profile in Familial Combined Hyperlipidemia Patients with Non-alcoholic Fatty Liver Disease

Abstract

Familial Combined Hyperlipidemia (FCHL) is the most common atherogenic lipid disorder, with FCHL patients representing 10-20% of premature myocardial infarction survivors. A significant overlap with non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) may suggest a common pathogenesis and explain the increased cardiovascular burden. Plasma levels of endogenous secretory receptor for advanced glycation-end-products (esRAGE), have been inversely associated with components of the MS, and may counteract RAGE-mediated pathogenesis, by acting as a decoy. We hypothesized that a ligand-RAGE pathway hyperactivity and inadequate endogenous protective response by esRAGE, as well as a number of pro-inflammatory and pro-atherothrombotic biochemical abnormalities, may be associated with the occurrence of NAFLD in a fraction of FCHL patients, even before and regardless of the diagnosis of MS. We performed a cross-sectional comparison among 72 patients with vs. 72 without NAFLD. Each group included FCHL alone, MS alone, and FCHL plus MS (n=24 each group). Regardless of the underlying biochemical abnormality (FCHL or MS), circulating esRAGE was significantly lower in patients with NAFLD as compared to their counterpart, in association with higher levels of CD40 ligand (CD40L), endogenous thrombin potential (ETP) and oxidized LDL and lower levels of IL-10 and adiponectin. MS and FCHL have additive effects on the above mentioned abnormalities. esRAGE was inversely related to CD40L and oxLDL and directly related to IL10 and adiponectin only in the groups with MS and NAFLD. Among patients with FCHL, those with the lowest esRAGE and highest degree of pro-inflammatory and atherothrombotic abnormalities coincide with the clinical diagnosis of NAFLD, regardless of MS, suggesting an interplay between adipokine secretion, oxidative stress and platelet/coagulative activation accelerating NAFLD occurrence as a proxy for cardiovascular disease.