Factores no genéticos modulan el papel de NR5A2 en la inflamación pancreáticaNon-genetic factors modulate the role of NR5A2 in pancreatic inflammation

Abstract

Genome-wide association studies have identified pancreatic ductal adenocarcinoma (PDAC) susceptibility variants in the vicinity of the NR5A2 gene, which codes for an orphan nuclear receptor involved in acinar differentiation. Nr5a2 heterozygous mice(Nr5a2+/-) display more severe damage upon induction of pancreatitis and are sensitized to the effects of mutant Kras. The pancreas of Nr5a2+/- mice displays a pre-inflammatory state that mimics transcriptomic changes present in the pancreas of subjects carrying NR5A2 risk alleles. Here, I aimed to determine the contribution of non-genetic factors to pancreatic inflammation in these mice. First, I investigated the effects of administration of a high fat diet (HFD). Wild type (wt) and Nr5a2+/- mice displayed similar changes in body weight gain, insulin resistance, glucose intolerance, and hypercholesterolemia. However, Nr5a2+/- mice presented an attenuated hepatic steatosis. While HFD administration exacerbated experimental pancreatitis in wt mice, this was not observed in Nr5a2+/- mice. These results indicate that Nr5a2 heterozygosity does not cooperate with HFD to induce pancreatic inflammation...