Comprehensive review on the pathogenesis of hypertriglyceridaemia-associated acute pancreatitis

Abstract

It is well known, that the inflammatory process that characterizes acute pancreatitis (AP) can lead to both pancreatic damage and systemic inflammatory response syndrome (SIRS). During the last 20 years, there has been a growing incidence of episodes of acute pancreatitis associated with hypertriglyceridaemia (HTAP). This review provides an overview of triglyceride metabolism and the potential mechanisms that may contribute to developing or exacerbating HTAP. The article comprehensively discusses the various pathological roles of free fatty acid, inflammatory response mechanisms, the involvement of microcirculation, serum calcium overload, oxidative stress and the endoplasmic reticulum, genetic polymorphism, and gut microbiota, which are known to trigger or escalate this condition. Future perspectives on HTAP appear promising, with ongoing research focused on developing more specific and effective treatment strategies.

Keywords: Hypertriglyceridemia; acute pancreatitis; lipids; mechanism; pathogenesis.

Figure 1.

Overview of potential mechanisms of hypertriglyceridaemia induced and aggravated AP. ① free fatty acids (FFAs) and ② microcirculatory disorder are considered vital factors in the mechanisms of hypertriglyceridaemia (HTG) induced acute pancreatitis (AP). microcirculatory disorder is primarily characterised by injuries caused by vasoconstriction/vasospasm, deceleration of blood flow, and blockage of blood vessels. ③ calcium (Ca²⁺) overload, ④ endoplasmic reticulum stress (ERS), ⑤ oxidative stress, ⑥ chemokines and cytokines, ⑦ genetic polymorphisms, and ⑧ gut microbiota are considered the potential mechanisms of HTG aggravated AP. Reactive oxygen species (ROS) are the main acting components in oxidative stress. Abbreviation: TG: triglyceride; cPLA: cytoplasmic phospholipase A; PKC: protein kinase C; ATP: adenosine triphosphate; UPR: unfolded protein responses; ROS: reactive oxygen species; DAMPs: damage-associated molecular patterns; NET: neutrophil extracellular trap.

Figure 2.

Triglyceride metabolism. ① endogenous triglycerides are synthesised from free fatty acids and glycerol in hepatocytes via the glycerol-3-phosphate pathway. Together with apolipoprotein (apo) B-100, they form VLDL particles. ② packaged triglyceride in the form of VLDL is then secreted into the blood circulation. ③ the VLDL particles are hydrolysed by lipoprotein lipase (LPL) in the plasma, producing progressively smaller particles and, eventually, intermediate density lipoprotein (IDL) particles. ④ some IDL particles undergo further catabolism in the blood by LPL or by hepatic lipase to generate low-density lipoprotein (LDL) particles. ⑤ others are taken up by hepatic cells and catabolised directly through binding to the LDL receptor or LDL receptor-related protein on hepatocytes. ⑥ exogenous dietary triglycerides are eventually absorbed by enterocytes (mainly in the small intestine) after a series of reactions in the intestinal tract, where they combine to apo B-48 to form chylomicrons (CM). ⑦ CM takes a rather circuitous route into the blood circulation. In the blood, CM is quickly hydrolysed by LPL along the luminal surface of the capillaries, resulting in the production of free fatty acids (FFA) and chylomicron remnants (CR). ⑧ the FFA enters the cells and is oxidised, not only for muscle energy but also for resynthesis with glycerol into triglycerides and stored in adipose tissue. ⑨ CR enters the hepatic circulation through a similar elimination pathway to some IDLs, by binding to LDL receptors or LDL receptor-related proteins.

Figure 3.

Mechanism of action of free fatty acids. ① excess triglycerides reach the vascular bed of the pancreas with blood transport in the form of triglyceride-rich lipoproteins. ② for idiopathic reasons, large amounts of lipase from pancreatic acinar cells are released into the blood through the vascular endothelium. ③ triglycerides are broken down by lipase into fatty acids and glycerol. ④ free fatty acids (FFAs) that exceed the albumin-binding capacity act directly on the vascular endothelium, ⑤ causing vascular damage such as endothelial dysregulation, vascular leakage and coagulation activation. ⑥ high concentrations of FFAs gradually aggregate into micelles with detergent like properties, causing ischaemia and subsequently triggering acidosis, trypsin activation, etc.

Figure 4.

Mechanisms of microcirculatory disorders. ① following the onset of hypertriglyceridaemia (HTG), progressive activation of cytoplasmic phospholipase A (cPLA), release of arachidonic acid (AA) and thromboxane A2 (TXA2)/prostaglandin (PGI2) imbalance through activation of p38 mitogen-activated protein kinase (MAPK), ultimately leads to vasoconstriction/vasospasm. ② stasis may occur after blood flow is slowed by HTG velocity, which in turn affects the ultrastructure of the vascular endothelium. ③ with an increase in triglyceride-rich lipoproteins, plasma viscosity rises, which can eventually lead to blockage of blood vessels. ④ as mentioned previously, free fatty acids (FFA) accumulate to form micelles, which can also block blood vessels. ⑤ FFA also acts directly on the pancreatic vasculature, causing vascular damage through increased permeability.

Figure 5.

Mechanisms of Ca²⁺ overload. ① high triglycerides and FFAs act as an irritant and cause pathological increases in intracellular calcium ions. Among these are unsaturated fatty acids (UFA), ② which cause dysfunction of mitochondrial complexes I and V. ③ the mitochondrial impairment leads to a reduction in ATP production, ④ followed by a progressive inhibition of the two ATP-dependent calcium channels (sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA) pumps and plasma membrane Ca²⁺ ATPase (PMCA) pumps), ⑤ preventing the normal clearance of intracellular calcium ions and eventually increasing their concentration. ⑥ the increase in calcium concentration causes calcium release-activated calcium channel protein 1 (ORAI1) to promote calcium ion entry into the cell, maintaining high toxic levels of calcium ion concentration. ⑦ the overload of calcium ions causes the permeable transition pore of the mitochondria to open in a state of high electrical conductivity, leaving the membrane potential required for ATP production deficient. ⑧ persistently elevated calcium ions most importantly causes elevated trypsinogen levels, and subsequent premature activation.

Figure 6.

Mechanisms of endoplasmic reticulum stress. Extra-pancreatic pathological irritation causes endoplasmic reticulum stress (ERS) by ① Increasing the demand for production of various enzymatic proproteins on the one hand, and by reducing the ability to process and recycle unwanted proteins through ② mitochondrial dysfunction and ③ dysfunctional autophagy on the other. ④ ERS has also been found to cause impaired autophagic blood flow in animal models of hypertriglyceridaemia associated AP. ⑤ The main feature of ERS is the unfolded protein response (UPR), which includes three pathways, inositol-requiring enzyme 1 (IRE1), transcription factor (ATF) 6, and protein kinase RNA-like endoplasmic reticulum kinase (PERK), corresponding to downstream spliced X-box binding protein 1 (sXBP1), cATF6, and ATF4, respectively. Some studies have found that palmitic acid in saturated fatty acids increases the expression of UPR-related proteins and various associated cytokines by affecting the splicing of the classical IRE1-sXBP1 pathway. ⑥ The production of several transcription factors under the action of UPR will act on the nucleus to promote gene transcription for endoplasmic reticulum expansion, molecular chaperone processes required for protein folding and endoplasmic reticulum-associated degradation, ⑦ allowing the endoplasmic reticulum to meet the demands of cellular metabolism and protein synthesis. ⑧ in addition, to some extent, they also initiate and promote the process of autophagy. ⑨ nevertheless, under prolonged endoplasmic reticulum stress, the above cycle fails to restore cellular homeostasis and will induce apoptosis via the C/EBP homologous protein (CHOP) pathway, promoting the process of pancreatitis.

Figure 7.

Mechanisms of oxidative stress. ①Animal studies have confirmed that in the hypertriglyceridaemia associated AP (HTAP) model, HTG induces the production of oxidative stress, which consists of an imbalance in the production of antioxidants (glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase) and pro-oxidants (pro-oxidant enzymes such as nicotinamide adenine dinucleotide phosphate oxidase (NOx) and catalase (CAT)) and an increased production of free radicals (FR, mainly reactive oxygen species (ROS)). ②NOx in pro-oxidants is one of the main sources of ROS. ③When ROS is mildly increased, it acts as a mediator of the inflammatory signalling pathway itself, enhancing the expression of chemokines, cytokines and adhesion factors, which in turn promote the inflammatory response; it also promotes leukocyte migration, activation and adhesion. Macrophages undergo a phenotypic shift in local infiltration, with polarisation towards the M1 type. ④Most notably, M1-type macrophages also promote cytokine production and ROS production. ⑤As the levels of ROS increase, cytotoxic effects are produced, causing pancreatic necrosis and promoting the process of HTAP. ⑥The effects of oxidative stress in the experimental model are manifested by depletion of GSH and lipid peroxidation (the metabolites are mainly lipid peroxide (LPO) and malondialdehyde (MDA)).

Figure 8.

Mechanisms of chemokines and cytokines. ①Free fatty acids (FFAs) increase C-X-C motif chemokine ligand 1 (CXCL1) and C-X-C motif chemokine ligand 2 (CXCL2), which bind to C-X-C chemokine receptors (CXCR2) and together chemotactic neutrophil aggregation and later form neutrophil extracellular traps (NETs) that activate pro-inflammatory signals to increase the release of inflammatory factors. ②Some species of FFAs can increase monocyte chemoattractant protein 1 (MCP-1) through activation of mitogen-activated protein kinase (MAPK)/janus kinase (JAK)-mediated nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways, which in turn chemotactic monocyte aggregation. ③FFAs can directly promote the release of inflammatory factors (TNF, IL-6, IL-1β, IL-18, etc.) and also indirectly increase the release of inflammatory factors through the above pathways. ④From animal models, it is concluded that FFAs are associated with an upregulation of protein kinase C (PKC) activity, which triggers calcium overload. ⑤When inflammation occurs and immune cells infiltrate the pancreas, this leads to necrosis and damage of pancreatic cells and the release of cellular contents. ⑥Damage-associated molecular patterns (DAMPs) are key cellular contents that are regulated by blockers through binding to immune cell receptors for inflammation. ⑦These cellular contents are important mediators of active monocytes, and activated monocytes play a very critical role in inflammatory injury and exacerbation.