The Effect Of4-phenyl Butyric Acid On Endoplasmic Reticulum Stress Of Pancreatic Beta-cells

Diabetes is a kind of metabolic disorder disease with chronichyperglycemia as the main characteristics, which is caused by a variety ofcauses. With the improvement of people’s living standard, the agingpopulation, lifestyle changes and advances in diagnostic techniques, thenumber of cases is increasing rapidly. The pathogenesis of diabetes is notyet clear, in which islet beta cells’dysfunction is one of the mainmechanisms for the onset of type2diabetes mellitus (T2DM), andendoplasmic reticulum stress (ERS) is closely related to the occurrence ofbeta cells’dysfunction. Therefore, it seems to be particularly necessary toseek a drug which can resist endoplasmic reticulum stress effect and canprotect the function of pancreatic beta cells from damaging. This papermainly discusses the effect of4-phenyl butyric acid (4-PBA) on ERS inpancreatic beta-cell of streptozotocin (STZ)-induced diabetic rats andRINm5F cells. This study established a T2DM model in SD rats withinjection of low dose STZ after being fed with high-fat diets, then after thefirst ten days rats in4-PBA treatment group were given500mg·kg-1·d-14-PBA suspension gavage for20days after modeling success.Radio-immune method was used to determine the changes of FFA, bloodglucose and serum insulin in each group. Hematoxylin-eosin staining wasused to observe islet morphology change, QT-PCR was used to detect theexpression changes of ERS and apoptosis-associated molecules (Caspase3,GRP78, CHOP) mRNA. At the same time,4-PBA was used to treatRINm5F cells occurred ERS induced by palmitic acid to make a furtherverification for the role of4-PBA on a cellular level. QT-PCR and Western blotting method was taken to detect the expression of ERS-associatedfactors at the mRNA and protein level. The study found that10days afterSTZ treatment, the concentration of blood glucose in T2DM and4-PBAtreatment group was higher than NC group and high-fat group(p<0.01),lower in body weight(p<0.01), which complies with diabetes expression,shows that the establishment of T2DM rats model was successful.20daysafter4-PBA treatment, compared with T2DM group, the concentration ofblood glucose in4-PBA treatment group was lower(p<0.05), the seruminsulin level was higher(p<0.05). Based on HE stained tissue sections, thestructure of pancreatic islet was disordered, unclear boundaries withsurrounding tissue and islet cells’numbers were decreased in T2DM group.While the structure of pancreatic islet in4-PBA treatment group was stillintacted and the numbers of pancreatic beta-cells were increased. The resultof QT-PCR shows that, the expression of GRP78and CHOP gene mRNAof T2DM group were significantly stronger compared with NCgroup(p<0.05), then declined after4-PBA treatment(p<0.01). Whenincubating RINm5F cells under a normal glucose concentration, comparedwith normal control group, the mRNA and protein expression of GRP78,CHOP and caspase3was increased significantly in palmitic acidstimulation group. After using different concentrations of4-PBA onRINm5F cells, mRNA and protein expression levels of CHOP and caspase3in10mmol·L-14-PBA treatment group was declined compared withpalmitic acid stimulation group. The mRNA expression of CHOP andcaspase3in2.5mmol·L-1and5mmol·L-14-PBA treatment groups wasincreased, but protein level of caspase3was declined and CHOP wasincreased. Combined animal and cell experiments, we believe that4-PBAmay reduce ERS through CHOP pathway, which has the effect of anti-ERSin islet β cell, and this protective effect may have a certainconcentration-dependent manner.