Lymphotoxin promotes acinar cell reprogramming and accelerates pre-neoplastic conversion in Kras induced pancreatic tumorigenesis

Abstract

Background: High dietary fat consumption, typical to obesity, is a risk factor and has a role in the etiology of pancreatitis and pancreatic cancer. Overload of dietary fatty acids (FAs) in non-adipose tissues is associated with cellular dysfunction, ER stress and cell death. Aims: We studies chronic and acute exposure of different FAs on exocrine acinar cells stress. Materials & methods: AR42J cells were challenged with different FAs for chronic and acute periods and cellular stress markers were studied. Results: We demonstrate that saturated FAs chronic overload induce an acinar cell lipotoxic effect expressed in triglycerides accumulation and prompted apoptotic process. As the effect of different dietary FAs on the exocrine pancreas ER stress response is unknown,we further studied the effect of acute challenge of different types of FAs (saturated, mono and poly-unsaturated) at normal and overload concentrations (typical to obesity) on fat accumulation and ER stress indicators (XBP splicing, UPR transcripts, immunohistochemistry) in exocrine pancreas acinar (AR42J) cells. We show that pancreatic acinar cells acutely challenged with different FAs exhibit significantly increased triglyceridesaccumulation.Acute challengewithsaturated FA in high concentration significantly increased stress levels, reflected by increased expression levels of inflammatory (TNF-a and TGFb), apoptotic and ER stress markers (Xbp1, CHOP, Bip and Xbp splicing). Treatment with mono and poly-unsaturated FAs did not significantly alter these markers. Conclusion: We demonstrate that different FAs affect acinar cell stress andmight exacerbate pancreatic pathologies in dietary fat overload, typical to obesity. The differential effect of the various FAs could have potential nutritional implications. Abstracts / Pancreatol S12