Hypertriglyceridemia Delays Pancreatic Regeneration After Acute Pancreatitis In Mice And Patients

Acute pancreatitis(AP)is a common digestive system disease.The annual incidence in the world is about 13-45 per 100,000,and it is gradually increasing.AP is usually induced by cholelithiasis,alcohol intake,and hypertriglyceridemia(HTG).It is characterised as an acute inflammatory injury of the pancreatic exocrine system.Pathological changes of the pancreas include edema,exudation,acinar cell necrosis and infiltration of inflammatory cells.After the pancreas undergoes a series of repair processes including inflammation fading,cell mesenchyme re-degradation,and acinar cell proliferation,the normal architecture is restored.However,some drugs such as morphine or metabolic diseases such as diabetes can delay the above repair process.HTG is a common metabolic disease,with clinical manifestations of elevated serum triglyceride(TG)levels.At present,HTG has become the second leading cause of AP in China,and the proportion of hypertriglyceridemic acute pancreatitis(HTG-AP)accounted for 13-25.6%of AP.HTG can increase the severity of AP,and the higher the serum TG level,the worse the patient’s prognosis.Previous studies have shown that HTG can affect myocardium and hepatocyte regeneration,but whether HTG affects AP after pancreatic repair is not yet clear.Therefore,the purpose of this study was to investigate the effect of HTG on the repair of pancreatic tissue after the onset of AP,and to deepen the understanding of the pathophysiology of HTG-AP.We first observed the relationship between serum TG levels and the degree of pancreatic repair in patients with severe acute pancreatitis(SAP).From January 2015 to December 2016,we performed long-term follow-up in patients with severe pancreatitis at the General Hospital of the Nanjing Military Region.After a 1-year follow-up,the patient was investigated for pancreatic repair after 1 year of discharge.Based on the highest TG level within 72 hours of disease onset,the patients were divided into four groups:normal triglyceridemia(NTG)(TG<1.7 mmol/L)and mild HTG(1.7-5.7 mmol/L),moderate HTG(5.7-11.3 mmol/L),and severe HTG(≥11.3 mmol/L).Due to the difficulty in obtaining pancreatic tissue in patients,taking into account the dynamic changes of exocrine function parallel to the repair of pancreatic tissue after the onset of AP,we used fecal elastase-1(FE-1),an classical markers of pancreatic exocrine function,indirectly assess the condition of pancreatic repair.According to the inclusion criteria and exclusion criteria,93 SAP patients were included in this study,and 20 patients failed to participate in the follow-up.Finally,11,37,11 and 14 patients in the NTG,mild,moderate,and severe HTG groups were examined for FE-1 level.There were no significant differences in other baseline characteristics between the four groups except serum TG levels.After analyzing the trend of FE-1 in the four groups,it was found that the higher the TG level,the lower the FE-1(Ptrend<0.001).The post-hoc analysis showed that the levels of FE-1 in patients with moderate and severe HTG were significantly lower than those in the NTG group,suggesting a negative correlation between serum TG levels and pancreatic repair in SAP patients.We further observed the effect of HTG on AP repair in animal models.Two animal models of HTG were used in animal experiments.One was poloxamer 407(P407)-induced HTG mice,and the other was glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1(GPIHBP1)gene-deficient mice.The animal model of HTG-AP was established by intraperitoneal injection of cerulein.The animals were killed after anesthesia on days 1,3,5,and 7 after the model establishment.The pathological changes of pancreatic tissue were dynamically observed.At the same time,through WB and immunohistochemical methods,changes in fibroblast inflammation related to pancreatic repair and acinar cell proliferation were dynamically observed.The experimental results showed that after 1 day of AP modeling,the pancreas of NTG and HTG mice showed significant acute pathological lesions.In the NTG group,the pancreatic tissue began to repair after 3 days of modeling,and the pancreas returned to its normal morphological structure on the 7th day.In the HTG group,the pancreas repair was significantly delayed,and the higher the level of serum TG,the slower the repair was.The morphological structure of the pancreas did not return to normal on the 7th day in the severe HTG group.Compared with mice in the NTG group,the HTG group mice were significantly delayed in the inflammatory reaction and acinar cell proliferation associated with AP repair.Finally,in order to determine whether lipid-lowering therapy can improve the course of HTG-AP repair,we applied the most commonly used TG-lowering drug,fenofibrate,to treat NTG mice and HTG mice 6 hours after AP modeling.The pathological changes of pancreas were observed in mice treated with different doses of fenofibrate(100mg/kg/d,200mg/kg/d,300mg/kg/d)for 1,3,and 5 days,and the effect on proliferation were observed by immunohistochemistry.The results showed that compared with the HTG-AP group,the TG levels were significantly decreased and acinar cell proliferation was enhanced on the third day after the 300 mg/kg/d dose in the fenofibrate treatment group.The area of pancreatic tissue necrosis on the 5th day was significant decreased,while 100 mg/kg/d and 200 mg/kg/d did not have this effect.In addition,the treatment with fenofibrate had no significant effect on the repair of AP after NTG mice.Our clinical studies and animal experiments have shown that HTG delays the repair process after AP,and the degree of repair is negatively correlated with serum TG levels.The use of fenofibrate for lipid-lowering therapy can promote pancreatic repair in HTG mice.The findings enriched the clinical understanding of AP injury repair and provided new ideas and theoretical basis for the treatment of HTG-AP.