Abstract
Hypertriglyceridemia severity is linked to acute pancreatitis prognosis, but it remains unknown why a portion of severe hypertriglyceridemia patients do not develop severe acute pancreatitis. To investigate whether hypertriglyceridemia subtypes affect acute pancreatitis progression, we analyzed two genetically modified hypertriglyceridemia mouse models—namely, glycosylphosphatidylinositol high-density lipoprotein binding protein 1 knockout (Gpihbp1−/−) and apolipoprotein C3 transgenic (ApoC3-tg) mice. Acute pancreatitis was induced by 10 intraperitoneal caerulein injections. Biochemical assays and pathological analysis were performed for the severity evaluation of acute pancreatitis. Plasma triglyceride-rich lipoproteins (TRLs), including chylomicrons and very low-density lipoprotein (VLDL), were collected via ultracentrifugation to evaluate their cytotoxic effects on primary pancreatic acinar cells (PACs). We found that the particle sizes of Gpihbp1−/− TRLs were larger than ApoC3-tg TRLs. Severe pancreatic injury with large areas of pancreatic necrosis in the entire lobule was induced in Gpihbp1−/− mice when plasma triglyceride levels were greater than 2000 mg/dL. However, ApoC3-tg mice with the same triglyceride levels did not develop large areas of pancreatic necrosis, even upon the administration of poloxamer 407 to further increase triglyceride levels. Meanwhile, in the acute pancreatitis model, free fatty acids (FFAs) in the pancreas of Gpihbp1−/− mice were greater than in ApoC3-tg mice. TRLs from Gpihbp1−/− mice released more FFAs and were more toxic to PACs than those from ApoC3-tg mice. Chylomicrons from patients showed the same effects on PACs as TRLs from Gpihbp1−/− mice. Gpihbp1−/− mice with triglyceride levels below 2000 mg/dL had milder pancreatic injury and less incidence of pancreatic necrosis than those with triglyceride levels above 2000 mg/dL, similar to Gpihbp1−/−mice with triglyceride levels above 2000 mg/dL but with fenofibrate administration. These findings demonstrated that hypertriglyceridemia subtypes with large TRL particles could affect acute pancreatitis progression and that chylomicrons showed more cytotoxicity than VLDL by releasing more FFAs.
Highlights
Hypertriglyceridemia is the cause of acute pancreatitis, and it leads to a poor prognosis[1,2,3,4,5]
Using a Malvern Zetasizer Nano, average and peak sizes of the plasma lipoprotein particles in Gpihbp1−/− mice were identified as significantly larger than those in ApoC3-tg mice (Fig. 1e). Their representative distribution is shown in Supplementary Fig. 1. This evidence suggested that large chylomicron particles are the main triglyceride-rich lipoproteins (TRLs) in Gpihbp1−/− mice, while small very low-density lipoprotein (VLDL) particles are the main TRLs in ApoC3-tg mice plasma
Two kinds of hypertriglyceridemia mouse models allowed us to compare the effects of different kinds of TRLs on the exacerbation of acute pancreatitis, and the large areas of pancreatic necrosis induced by 10 caerulein injections in Gpihbp1−/− mice allowed us to examine the special effects of large TRL particles almost at a glance
Summary
Hypertriglyceridemia is the cause of acute pancreatitis, and it leads to a poor prognosis[1,2,3,4,5]. Therapeutic guidelines for hypertriglyceridemia-associated acute pancreatitis are not well established. Fully understanding the mechanisms of acute pancreatitis under hypertriglyceridemia will be potentially valuable for clinical practice. Official journal of the Cell Death Differentiation Association. The pathogenesis of hypertriglyceridemia is complex and leads to multiple phenotypes enriched with various triglyceride-rich lipoproteins (TRLs) in plasma, including chylomicrons and/or very low-density lipoprotein (VLDL). It was reported that the subtypes were associated with acute pancreatitis episodes[11,12,13,14] in the clinic, their relationship with prognosis and their underlying mechanisms are worth exploring
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