Development of a novel model of hypertriglyceridemic acute pancreatitis in mice

Yiyuan Pan,Lei Meng,Shufeng Liu,Zhihui Tong,Qi Yang,Guotao Lu,Jieshou Li,Yizhe Chen,Weiqin Li,Lin Gao,Baiqiang Li,Yong Li,Yuhui Wang,George Liu,Bo Ye

doi:10.1038/srep40799

Abstract

The morbidity rate of hypertriglyceridemic acute pancreatitis (HTG-AP) increased rapidly over the last decade. However an appropriate animal model was lacking to recapitulate this complicated human disease. We established a novel mice model of HTG-AP by poloxamer 407 (P-407) combined with caerulein (Cae). In our study, serum triglyceride levels of P-407 induced mice were elevated in a dose-dependent manner, and the pancreatic and pulmonary injuries were much severer in HTG mice than normal mice when injected with conventional dose Cae (50 ug/kg), what’s more, the severity of AP was positively correlative with duration and extent of HTG. In addition, we found that a low dose Cae (5 ug/kg) could induce pancreatic injury in HTG mice while there was no obvious pathological injury in normal mice. Finally, we observed that HTG leaded to the increased infiltrations of macrophages and neutrophils in mice pancreatic tissues. In conclusion, we have developed a novel animal model of HTG-AP that can mimic physiological, histological, clinical features of human HTG-AP and it could promote the development of therapeutic strategies and advance the mechanism research on HTG-AP.

Highlights

Mice[12,13] is difficult to get
Consistent with the previous outcomes of Professor Saja[17], we found that Poloxamer 407 (P-407) could elevate the serum ApoCIII levels which affected the metabolism of triglyceride and induced hypertriglyceridemia (Fig. S1A)
The result of fast protein liquid chromatography (FPLC) further validated this phenomenon and indicated that hyperlipidemia in mice induced by P-407 was mainly composed of very low-density lipoprotein (Fig. S1C,D)

Summary

Introduction

Mice[12,13] is difficult to get. Poloxamer 407 (P-407) is a hydrophilic triblock copolymer comprised of polyoxyethylene and polyoxypropylene units and has been reported to induce HTG with little side effects[14]. Physiological toxicity of P-407 is so low that both short-term and long-term use can induce high serum triglyceride levels in mice[14]. Saja et al.[17] found that serum triglyceride level of mice could rise up to 4000 mg/dl after treated with P-407 for 28 days and long-term HTG can cause lipid deposition in heart, liver and kidney with infiltration of macrophages and other pathological changes. We put forward that using P-407 to establish HTG model, inducing AP by intraperitoneal injection caerulein (Cae) to build a HTG-AP mice model which provides feasibility for the mechanism study of HTG-AP

Methods

Results

Conclusion