Cross-talk between Insulin Resistance and FAT Atypical Cadherin 1 (FAT1) in Patients with Nonalcoholic Fatty Liver Disease

GAZZI C; PIROLA CJ; SOOKOIAN S; CASTANO GO; GARAYCOECHEA M; FLICHMAN D

San Francisco

Congreso; 69th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2019; 2018

American Association for the Study of Liver Diseases

FAT1 gene is an ortholog of the Drosophila fatgene that encodes a tumor suppressor essential for controllingcell proliferation; the gene is a member of the cadherinsuperfamily. Its product functions as an adhesion molecule and/or signaling receptor that regulates cell communication, actincytoskeletal organization, and liver-wound healing response.Aim: We postulated that the deleterious association betweeninsulin resistance and NAFLD might be explained by changesin the pattern of liver FAT1-gene expression. Likewise, FAT1-liver abundance might be modulated by lncRNAs. Methods:We included a sample of 125 liver-tissue specimens linked toclinical, biochemical, and histological records of patients ina two-stage study design (exploratory-stage: morbidly-obesepatients with NAFLD, n = 54 and normal liver histology, n=22; replication-stage: patients with NAFLD and MetabolicSyndrome, n =41). We searched for differentially expressedlevels of FAT1-mRNA, as well as we explored the pattern ofliver expression of two lncRNAs: FENDRR (FOXF1 AdjacentNon-Coding Developmental Regulatory RNA), a LncRNA thatis involved in the epigenetic modification of gene promoters,and TUG1 (Taurine-up-regulated gene 1), which regulatesmitochondrial bioenergetics. Target genes were normalizedto the housekeeping gene expression (RPL19, RibosomalProtein L19). ANCOVA and multiple regression analysiswere performed using log-transformed variables. Results:We found that FAT1-mRNA abundance was 5.27-fold upregulatedin the liver of patients with NAFLD (p=0.017) in thepooled analysis.. We further observed a positive correlationof FAT1-mRNA levels in liver tissue-specimens and HOMA-IR(Spearman R: 0.42, p=0.000026) and fasting plasma insulinlevels (R: 0.42, p=0.000031). The upregulation of FAT1 wasindependent of HOMA-IR (6.10 fold, p=0.018) but there was atrend to be higher in NAFLD patients with insulin resistance.We asked whether the abundance of FAT1 is linked to theexpression of the lncRNA-FENDRR, and we found thatboth transcripts were significantly and positively correlated(beta: 0.57, p=0.000028) independently of HOMA-IR andNAFLD. In addition, we found that transcript levels of FAT1and TUG1 were negatively correlated (R:-0.64, p=0.00029).Conclusion: Our study suggests a putative novel molecularlink between NAFLD, insulin resistance, and the adhesionmolecule-FAT1, which might be modulated by the lncRNAsFENDRR and TUG1.