Abstract
Dietary fat overload (typical to obesity) increases the risk of pancreatic pathologies through mechanisms yet to be defined. We previously showed that saturated dietary fat induces pancreatic acinar lipotoxicity and cellular stress. The endoplasmic reticulum (ER) of exocrine pancreas cells is highly developed and thus predisposed to stress. We studied the combination of saturated and unsaturated FAs in metabolic and pancreatitis like cerulein (CER)-induced stress states on cellular ER stress.Exocrine pancreas AR42J and rat primary exocrine acinar cells underwent acute (24 h) challenge with different FAs (saturated, monounsaturated) at different concentrations (250 and 500 µM) and in combination with acute CER-induced stress, and were analyzed for fat accumulation, ER stress unfolded protein response (UPR) and immune and enzyme markers. Acute exposure of AR42J and pancreatic acinar cells to different FAs and their combinations increased triglyceride accumulation. Palmitic acid significantly dose-dependently enhanced the UPR, immune factors and pancreatic lipase (PL) levels, as demonstrated by XBP1 splicing and elevation in UPR transcripts and protein levels (Xbp1,Atf6, Atf4, Chop, Tnfα, Tgfβ and Il-6). Exposure to high palmitic levels in a CER-induced stress state synergistically increased ER stress and inflammation marker levels. Exposure to oleic acid did not induce ER stress and PL levels and significantly decreased immune factors in an acute CER-induced stress state. Combination of oleic and palmitic acids significantly reduced the palmitic-induced ER stress, but did not affect the immune factor response. We show that combination of monounsaturated and saturated FAs protects from exocrine pancreatic cellular ER stress in both metabolic and CER-induced stress.
Highlights
Obesity and high fat diet (HFD) are risk factors in the etiology of pancreatitis and pancreatic cancer [1]
We explored the effects of the combination of both FAs (PAL and oleic acid (OL), at concentrations typical of normal and obese states) on endoplasmic reticulum (ER) and immune stress markers combined with CER-induced stress in exocrine in-vitro AR42J and ex-vivo primary acinar cell models
We studied the effect of treatment with the FAs OL and palmitic acid (PAL) (250 μM) and their combination (1:1 ratio), with or without induction of stress (CER), on splicing of Xbp1 mRNA in primary cells
Summary
Obesity and high fat diet (HFD) are risk factors in the etiology of pancreatitis and pancreatic cancer [1]. Exposure to high levels of FAs when PAL is part of the combination, with or without CER, resulted in significant elevation in Tgf–β transcript levels compared with control untreated cells, and to OL with or without CER.
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