Kalıtsal Metabolik Hastalıklarda Otofaji, Oksidatif Stres ve İnflamasyon İlişkisi

Abstract

The complications such as epilepsy, cataract, hepatic failure, chronic renal disease may develop during the clinical follow-up of the patients with inherited metabolic diseases. The aim of this study is to investigate the role of autophagic dysfunction, inflammation and oxidative stress in the development of these complications. Forty-eight patients with the diagnosis of classic galactosemia, maple syrup urine disease, hereditary tyrosinemia type 1, lysinuric protein intolerance and ten healthy children were included in the study. Laboratory investigations were performed such as analysis of autophagy ( Beclin 1, LC3B-II, p62) and inflammasome (NLRP3, ASC, Caspase 1, NF-Ƙβ) gene and protein expressions, measurement of oxidative stress biomarkers (total thiol, native thiol, disulphid, thiol/disulphide homeostasis, total antioxidant capacity and total oxidative stress), cytokine levels, immune phenotyping with lymphocyte subgroup and lymphocyte activation markers, metabolomic analysis with untargeted metabolomic profiling in the patient and healthy control group. The highest levels of total thiol, native thiol, TOS and TAS were observed in MSUD group. The highest disulphide, the lowest TAC levels were detected in LPI groups. The cytokine levels showed no significant difference between patient and control group. In all groups, NLRP3/p62 gene expressions increased. The highest fold changes were observed in the patients of galactosemia and LPI groups. Autophagy dysfunction was detected in all groups. NLRP3/p62 gene expressions were positively correlated. p62 seems to be a key player which links the antioxidant (Nrf2), autophagy and inflammation pathways in the patient groups. NLRP3 gene expressions were found to be higher with specific clinical phenotypes such as cataract in galactosemia patients, lung involvement in LPI group or hepatic fibrosis in tyrosinemi patients. Significant statistical differences were observed with respect to T and B lymphocyte, DNT, NKT, CD3HLADR, classic and non-classic monocyte levels in the patient groups. PLS-DA analysis revealed statistically significant different metabolites in the patient group compared with healthy control group. The metabolites enriched in general metabolic pathways such as steroid hormone and aminoacid biosynthesis, lipid, purine-pyrimidine metabolism, energy metabolism were principally detected by metabolomic analysis in the patient group. The metabolomic profiling of LPI patients were resembling with the pathways affected in chronic inflammatory diseases. This is the first study which investigates the inflammasome and autophagy gene and protein expressions, the relationship between oxidative stress, autophagy and inflammation, immun functions and metabolomic profiling simultaneously in intoxication type inherited metabolic diseases. The results of the study revealed that autophagic dysfunction, oxidative stress, inflammation, immun dysregulation might play an important role under the pathogenesis of metabolic diseases.