Targeting ApoA5‐Associated Hypertriglyceridemia to Ameliorate Acute Pancreatitis: Insights From a Knockout Hamster Model

Dear Editor. While gallstones and alcohol are leading causes of acute pancreatitis (AP), emerging evidence highlights a significant role for genetic and metabolic factors, particularly in recurrent AP (RAP) [1]. Among them, severe hypertriglyceridemia (HTG) is a key risk factor, though its mechanistic link to AP remains unclear. Previous studies have demonstrated that several mutations in human genes regulating triglyceride metabolism, in which APOA5 is one of the most common genetic abnormalities in RAP patients [2]. However, the relationship between ApoA5 and HTG-AP has not been well investigated in experimental animals. Recently, we developed Apoa5 knockout (Apoa5−/−) golden hamster model that reproducibly exhibited severe HTG, closely resembling human familial chylomicronemia syndrome [3]. Importantly, we observed that the activation of UCP1 in brown adipose tissue (BAT) by cold exposure or the β3-adrenergic receptor agonist CL316243 administration could significantly correct severe HTG and hepatic steatosis in Apoa5−/− hamsters [3]. The incidence of AP serves as a key metric for evaluating the therapeutic effectiveness of triglyceride-lowering agents in clinical trials; however, whether correction of severe HTG can improve the outcome of HTG-associated RAP has not been investigated in our hamster model yet. In the present study, it is rational for us to further investigate the relationship between BAT activation and pancreatic pathology in the context of ApoA5 deficiency. In agreement with the previous findings [4], AP was established in this hamster model by intraperitoneal caerulein injection (Figure 1A and Supporting information). Plasma triglyceride and amylase levels in Apoa5−/− hamsters were significantly increased compared with WT controls. Histological examination revealed markedly aggravated pancreatic injury in Apoa5−/− animals. Consistently, histopathological scores were significantly increased compared with WT controls. Myeloperoxidase expression and apoptotic bodies were increased in pancreas of Apoa5−/− hamsters, indicating enhanced local inflammation and cell death. Moreover, mRNA expression profiling demonstrated an upregulation in proinflammatory cytokines (Tnfα, Cd68), the apoptotic marker Bax, and a downregulation in the anti-inflammatory cytokine Il10 (Figure 1B). To our knowledge, it is very difficult to treat familial HTG. However, we found unexpectedly that acting through stimulation of BAT metabolism significantly reduced plasma triglyceride levels in Apoa5−/− hamsters [3]. Herein, we tested whether this therapeutic avenues could improve pancreatic outcomes in Apoa5−/− hamsters with AP. Cold exposure at 4°C for 16 h significantly lowered plasma triglycerides (Figure 1C) and then ameliorated pancreatic pathological injury. Similarly, treatment with CL316243 to activate BAT led to a substantial reduction in plasma triglyceride levels, as well as an improvement of pancreatic histopathology (Figure 1D). In summary, our study establishes Apoa5 deficiency as a potent genetic driver of HTG-AP through chylomicron accumulation in circulation. Importantly, we show that pharmacologic or environmental activation of BAT-associated lipid metabolism can reverse the pathological features of HTG-AP, offering a clinically translatable, nonviral, and low-risk strategy. Our findings underscore the importance of genetic screening and triglyceride monitoring in RAP patients, supporting the development of metabolism-targeted therapies as a novel approach to treat HTG-AP. However, it should be noted that the species differences in ApoA5 biology, BAT activity, and dietary influences cannot be excluded when translating the findings reported in hamster model to humans, which need to be further studied in future. Study concept and design: Yuhui Wang and Xunde Xian. Experiments: Sijing Shi, Kaikai Lu, Yijun Tao, Ling Zhang, and Yue Zhang. Acquisition, analysis, or interpretation of data: Sijing Shi and Kaikai Lu. Drafting of the manuscript: Sijing Shi, Kaikai Lu, Geoger Liu, Wei Huang, Yuhui Wang, and Xunde Xian. Critical revision of the manuscript for important intellectual content: Yuhui Wang and Xunde Xian. Obtained funding: Yue Zhang, Yuhui Wang, and Xunde Xian. Final approval of manuscript as submitted: Xunde Xian. Guarantor of the article: Xunde Xian. All authors have read and approved the final manuscript. We are indebted to Qiang Shen (Institute of Cardiovascular Sciences, Peking University) for excellent technical assistance. This work was supported by the National Natural Science Foundation of China (NSFC) 82270479 and HY2021-1; Peking University Medicine plus X Pilot Program-Platform Construction Project 2024YXXLHPT010 to X.X.; the Beijing Natural Science Foundation Z230017 to Y.W.; the Jiangxi Provincial Natural Science Foundation 20212BAB216022 to Y.Z. All experiments were approved by the Laboratory Animal Ethics Committee of Peking University (Approval No. LA2022147). The authors declare no conflicts of interest. The data generated are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.