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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.
Source publication
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 overvie...
Citations
... 3 These FFAs subsequently induce inflammation, ischemia, and tissue damage. 1,4 While it accounts for a small percentage of all acute pancreatitis cases, HTG-AP can lead to substantial morbidity and mortality if not promptly managed. 5,6 Common risk factors associated with HTG-AP include poorly controlled T2DM and underlying hyperlipidemia. ...
Background
Hypertriglyceridemia (HTG) is a known but relatively uncommon cause of acute pancreatitis (AP), accounting for approximately 1–7% of cases. Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) can lead to significant morbidity if not promptly identified and managed. This case report describes a patient with poorly controlled type 2 diabetes mellitus (T2DM) who presented with HTG-AP, characterized by a lipemic blood sample, in a resource-limited setting.
Case Presentation
A 45-year-old male with a history of poorly controlled T2DM and hyperlipidemia presented with a 24-hour history of severe epigastric abdominal pain, fatigue, and vomiting. Clinical examination revealed diffuse abdominal tenderness, tachypnea, tachycardia, and a habitus consistent with central obesity. His BMI was 33.2 kg/m². Initial laboratory findings included seriously elevated triglycerides (1509 mg/dL), lipase (83 U/L), and amylase (161 U/L), along with hyperglycemia (465mg/dL). Abdominal computed tomography (CT) scan showed peripancreatic fatty stranding, consistent with early acute pancreatitis, as well as a fatty liver and a focal hypodense lesion in the right lobe. Treatment included intravenous insulin, dextrose, and potassium infusions to reduce triglyceride levels, analgesics, intravenous fluids for electrolyte imbalances, and thromboprophylaxis with enoxaparin.
Conclusion
This case highlights the importance of early recognition of HTG-AP in patients with poorly controlled diabetes and hyperlipidemia. Prompt triglyceride-lowering therapy, primarily with insulin in resource-limited settings, is crucial for improving patient outcomes and preventing complications.
... Viral infections, such as mumps and coxsackievirus, as well as hematological conditions, such as hypertriglyceridemia, can also trigger pancreatitis. elevated triglyceride levels result in the formation of lipid droplets that obstruct the pancreatic ducts and facilitate PAC injury and inflammation (18). ...
... 3) some studies have shown that TG ≥ 5.65 mmol/L can trigger AP, especially when there is chylomicronemia or secondary factors (such as diabetes, pregnancy) [29,30,35]. 4) the mechanism by which HTG leads to AP, (such as free fatty acid toxicity, pancreatic microcirculation disorders) may have threshold differences among different individuals [40,41]. While 71.4% of the studies reported an increasing trend in the proportion of HTG-AP among AP cases over time, this trend lacked statistical significance (P > 0.05). ...
This systematic review aims to comprehensively assess the epidemiology and identify risk factors associated with the severity and recurrence of hypertriglyceridemia-induced acute pancreatitis (HTG-AP). A search of PubMed, Web of Science, and Cochrane databases was conducted to identify all relevant randomized controlled trials (RCTs), prospective, or retrospective cohort studies on HTG-AP. Data related to epidemiology and risk factors for severity and recurrence of HTG-AP were extracted and analyzed. Seventy-seven studies met the inclusion criteria, comprising 1 RCT, 21 prospective studies, and 55 retrospective studies. A total of 56,617 acute pancreatitis (AP) patients were included, of which 19.99% were diagnosed with HTG-AP (n = 11,315). Compared to non-HTG-AP patients, HTG-AP patients were more likely to be male (68.7% vs. 57.3%) and younger (mean age 41.47 ± 4.32 vs. 50.25 ± 7.70 years). HTG-AP patients exhibited higher mortality rates (up to 20% vs. 15.2%), increased severity (8.3% to 100% vs. 3.8% to 47.2%), and higher recurrence rates (up to 64.8% vs. 23.3%). Analysis of temporal trends from 2002 to 2023 showed a range of HTG-AP prevalence in overall AP patients from 1.6% to 47.6%, with a slight upward trend that was not statistically significant (P = 0.1081). Regional analysis indicated relatively stable prevalence in North America (P = 0.5787), Europe (P = 0.0881), other regions (P = 0.738), while prevalence in China showed a significant increase (P = 0.0119). Thirteen studies investigated risk factors affecting HTG-AP severity, with elevated serum triglyceride (TG) levels associated with increased risk of complications such as pancreatic necrosis, systemic inflammatory response syndrome (SIRS), shock, and multi-organ failure. Additional factors including high neutrophil-to-lymphocyte ratio (NLR), elevated levels of amylase and C-reactive protein (CRP), hypocalcemia, and hypoalbuminemia were also implicated in HTG-AP severity. Smoking history, poor lipid control (TG > 3.1 mmol/L), or recurrent hypertriglyceridemia during follow-up were identified as potential predictors of HTG-AP recurrence. Our findings indicate a stable global prevalence of HTG-AP within AP patients, but a notable increase in China, possibly attributed to socio-economic and dietary factors.
... Cer have been well-documented to promote inflammation through activation of diverse signaling pathways 18 . The accumulation of TGs and DGs has been shown to trigger inflammatory responses in pancreatic tissue 19 . These changes coincided with suppression of polyunsaturated fatty acids (PUFAs) at toxic doses of ASNase (Figure 3H). ...
Poor therapeutic index is a principal cause of drug attrition during development. A case in point is L-asparaginase (ASNase), an enzyme-drug approved for treatment of pediatric acute lympho-blastic leukemia (ALL) but too toxic for adults. To elucidate potentially targetable mechanisms for miti-gation of ASNase toxicity, we performed multi-omic profiling of the response to sub-toxic and toxic doses of ASNase in mice. We collected whole blood samples longitudinally, processed them to plasma, and extracted metabolites, lipids, and proteins from a single 20-µL plasma sample. We analyzed the extracts using multiple reaction monitoring (MRM) of 500+ water soluble metabolites, 750+ lipids, and 375 pep-tides on a triple quadrupole LC-MS/MS platform. Metabolites, lipids, and peptides that were modulated in a dose-dependent manner appeared to converge on antioxidation, inflammation, autophagy, and cell death pathways, prompting the hypothesis that inhibiting those pathways might decrease ASNase toxicity while preserving anticancer activity. Overall, we provide here a streamlined, three-in-one LC-MS/MS workflow for targeted metabolomics, lipidomics, and proteomics and demonstrate its ability to generate new insights into mechanisms of drug toxicity.
... Triglycerides are broken down by the pancreatic lipase into free fatty acids, which cause lipotoxicity. The severity of injury to the pancreas depends mainly on inflammatory response and lipotoxicity-induced damage to the pancreas [11][12][13]. ...
... A quicker and more effective approach increases the likelihood of survival and prevention of complications in the patients of AP [1,4,6]. Recently, various studies have shown that serum triglyceride (TG) level is a valuable predictor of acute pancreatitis (AP) severity and clinical outcomes of AP [10,11]. The simplicity, cost-effectiveness, and rapid availability of TG test results make them particularly useful. ...
... The resulting inflammatory cascade amplifies pancreatic injury, leading to the increased severity of acute pancreatitis. An increased serum TG levels indicate an imbalance between these immune responses, predicting poor outcomes as the unchecked inflammatory response causes tissue damage, organ dysfunction, and increased mortality [11,12]. ...
Background
Acute pancreatitis (AP) is a potentially fatal condition with a poor prognosis if it escalates to its severe form. The pathophysiology of AP has been associated with serum triglyceride (TG) levels. However, the relationship between serum triglyceride (TG) levels and AP severity remains poorly understood. Therefore, this study aimed to investigate the correlation between serum TG levels and the severity of AP.
Methods
This retrospective study was conducted at Benazir Bhutto Hospital (BBH) in Rawalpindi, Pakistan, from January 2023 to January 2024, among 210 patients with AP. Data was gathered on a self-devised proforma from medical records. The Ranson criteria score was utilized to assess the severity of AP. Patients were divided into two groups: patients with non-severe AP and patients with severe AP on the basis of their Ranson criteria score. Data analysis was done in the Statistical Package for Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY) through the chi-squared test, independent t-test, Pearson's correlation, and a simple linear regression analysis. The p-value of less than 0.05 was set as significant.
Results
Of the 210 patients, 135 (64.28%) had non-severe AP, while 75 (35.72%) had severe AP. Values of the variables including gender, age, white blood cell (WBC) count, serum aspartate transaminase (AST) levels, serum blood glucose levels, serum lactate dehydrogenase (LDH) levels, Ranson score, serum amylase levels, serum lipase levels, body mass index, serum TG levels, and length of hospital stay were significantly (p < 0.05) higher among the patients with severe AP. Pearson's correlation indicated that serum TG levels were positively and significantly associated with the Ranson scores (coefficient {r} = 0.80; p < 0.003). Moreover, linear regression analysis confirmed serum TG level as a significant predictor of AP severity, with a beta coefficient (β) of 3.21 and a 95% confidence interval (CI) of 1.82-4.72 (p < 0.002). The frequency of clinical outcomes such as pancreatic necrosis, intensive care unit (ICU) admission, and mortality was significantly higher among the patients with elevated serum TG levels.
Conclusions
In the current study, elevated serum TG level was found to be an independent predictor of the increased severity of AP, as suggested by higher Ranson scores and adverse clinical outcomes among the patients with raised serum TG levels. This current study supports the use of serum TG level as a reliable tool for the prompt identification of high-risk AP patients, facilitating timely interventions and improved outcomes.
... Both increased secretion and impaired hepatic clearance of TG induce the accumulation of cholesterol-enriched TRL remnants of <70 nm size, which can enter the subendothelial space and reinforce proatherogenic processes [20]. Furthermore, at extremely high TG levels, excessive amounts of free fatty acids generated by TG hydrolysis inhibit mitochondrial complexes in acinar cells, triggering cytokine release and tissue necrosis-a mechanism proposed to explain the pathogenesis of HTG-induced pancreatitis [21]. Due to the central role in TRL catabolism, LPL-mediated lipolysis has appeared as a novel treatment target for HTG [22]. ...
Hypertriglyceridemia (HTG) is associated with a residual risk of atherosclerotic cardiovascular disease. Extremely elevated triglyceride (TG) concentrations, particularly due to familial chylomicronemia syndrome (FCS), pose a risk for acute pancreatitis. Standard therapies with statins, fibrates, omega-3 fatty acids, and niacin may be insufficient to reduce elevated TG levels and improve clinical outcomes in patients with HTG. Novel antisense oligonucleotides and small interfering ribonucleic acids target the key modulators of TG-rich lipoprotein catabolism. Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG.
... 4 AP is often accompanied by two major clinical courses, the first one is systemic inflammatory response syndrome (SIRS) and the other one is compensatory antiinflammatory response syndrome (CARS). 5 The former course usually occurs early and lasts for 1 or 2 weeks. The latter ranges from a few weeks to a few months and is characterized by the presence of local complications and related infectious complications that often occur in the later stage of the disease and usually last for a rather long time. ...
Objective
Patients with acute pancreatitis (AP) complicated by carbapenem-resistant Enterobacteriaceae (CRE) infection often have a higher mortality rate. However, little investigation on the risk factor analysis has been published for the AP complicated by CRE. Therefore, this study conducted a retrospective analysis of the clinical characteristics, risk factors, and molecular epidemiological features associated with CRE infection in patients with AP.
Methods
A total of 240 patients with AP were admitted to our hospital from 2011 to 2021 as the research objects, and were divided into a CRE group of 60 cases and a non-CRE group of 180 cases based on whether they were co-infected with CRE or not. Furthermore, both univariate analysis and multivariate analysis were used to analyze the risk factors of AP co-infection with CRE. In the CRE group, polymerase chain reaction (PCR) and agarose gel electrophoresis (AGE) were used to detect the expression of five common carbapenemase genes including blaKPC, blaIMP, blaVIM, blaNDM, and blaOXA-48.
Results
The pathogenic bacteria in the CRE group are composed of Klebsiella pneumonia at 35.00%, Escherichia coli at 33.33%, Enterobacter cloacae at 25.00%, and Citrobacter freundii at 6.67%. Multivariate analysis showed that APACHE-II scores (OR=1.22), history of abdominal surgery (OR=81.82), and ERCP (OR=3.66) were independent risk factors for AP co-infection with CRE (P<0.05). About half (18/40) of the CRE carried carbapenemase genes. blaKPC was the major carbapenemase gene.
Conclusion
There are many risk factors for AP co-infection with CRE, which can occur in patients with high APACHE-II scores, experienced ERCP, and a history of abdominal surgery.
... Extensive research into the mechanisms by which lipids initiate AP has highlighted the crucial role of inflammatory activation. Hypercholesterolemia compromises vascular endothelial cells by impairing nitric oxide synthesis and causing dysfunction of endothelial progenitor cells, while also promoting microinflammation of the endothelium 6 . In animal models, high-fat diets have been found to exacerbate intestinal barrier injuries through the TLR4-RIP3 pathway in severe AP 7 . ...
Acute pancreatitis (AP) is a severe gastrointestinal condition with an increasing incidence of hyperlipidemic etiology. The investigation employed a two-sample, bidirectional Mendelian randomization method to investigate potential causal relationship between lipidome profiles, inflammatory mediators, and AP. Exploration of genetic variants across the genome in a study population of 10,630 AP cases and 844,679 non-AP individuals revealed multiple lipidome entities significantly associated with AP risk. The study identified 23 lipid species with unidirectional causal effects on AP after accounting for heterogeneity, pleiotropy, and potential reverse causation. Additionally, five inflammatory factors (CD5, IL-13, MMP-1, STAMBP, TNFRSF9) showed significant potential causal relationship with AP. Further analysis elucidated the intricate interplay between specific lipid species and inflammatory mediators in influencing AP incidence. Notably, Sterol ester (27:1/20:4) and several phosphatidylcholine species, including PC (17:0_20:4), PC (18:0_20:4), PC (18:0_20:5), and PC (O-18:2_20:4), were negatively associated with AP risk. This protective effect was partially mediated through decreased levels of inflammatory markers, particularly STAMBP and MMP-1. The study found that these phosphatidylcholines and sterol esters significantly reduced the levels of these pro-inflammatory factors, thereby potentially mitigating AP risk. Conversely, Phosphatidylinositol (16:0_18:1) demonstrated a positive association with AP risk. This detrimental effect was partially mediated by increased levels of MMP-1 and STAMBP, suggesting a pro-inflammatory mechanism. The study provides evidence that this specific phosphatidylinositol species may exacerbate AP risk by promoting inflammatory pathways. These findings elucidate the complex interplay between lipid metabolites, inflammation, and AP pathogenesis, potentially informing novel therapeutic strategies. The study highlights the utility of Mendelian randomization in uncovering potential causal relationship in AP. It underscores the requirement for further study into the molecular mechanisms underlying lipid-mediated inflammation in AP, particularly the roles of phosphatidylcholines and sterol esters in modulating inflammatory responses. Further studies are warranted to confirm our observations in laboratory models and assess their translational value in developing AP preventive and therapeutic strategies.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-85354-y.
... Oxidative stress is characterized by a state of imbalance in which an excessive reactive oxygen species (ROS) amount is generated, depleting endogenous antioxidants and then promoting cellular injury and molecular peroxidation [7]. Excessive ROS release has been well documented in the HLAP, leading to pancreatic necrosis and worsening disease severity [8]. On the other hand, the production in surplus of free cholesterol in the endoplasmic reticulum and mitochondria also leads to oxidative stress and sensitizes cells to cytokines and cell death [9]. ...
... A previous study has highlighted that the mitogen-activated protein kinase (MAPK)/ nuclear factor kappa B (NF-κB) pathways play an essential role in the process of AP [10]. High levels of TG could activate the MAPK pathways and lead to the disturbance of the vasoconstriction/vasospasm and the impairment of pancreatic microcirculation [8]. Free fatty acids (FFA), the main component of TG, can bind to Toll-like receptors and, in this way, upregulate the expression of NF-κB and in-duce the release of inflammatory cytokines [8]. ...
... High levels of TG could activate the MAPK pathways and lead to the disturbance of the vasoconstriction/vasospasm and the impairment of pancreatic microcirculation [8]. Free fatty acids (FFA), the main component of TG, can bind to Toll-like receptors and, in this way, upregulate the expression of NF-κB and in-duce the release of inflammatory cytokines [8]. It may also promote monocyte aggregation by producing monocyte-chemoattractant protein 1 through the activation of MAPK/Janus kinase (JAK)-mediated NF-κB and signal transducer and activator of transcription 3 (STAT3) pathways [8]. ...
Background: The mechanisms involved in the hyperlipidemia-associated acute pancreatitis (HLAP) is not yet fully understood.
Aims: To investigate the role of P38MAPK (mitogen-activated protein kinases) and oxidative stress in the pathogenesis of HLAP.
Methods: In AP (acute pancreatitis) patients, the GEO database retrieved gene expression profiles of cytokines, MAPK14, nuclear factor kappa B subunit 1 (NF-κB 1) and superoxide dismutase 2 (SOD 2). GeneMANIA has been used for the prediction of potential interaction mechanisms. Validation was carried out using an experimental AP model and a bi-directional Mendelian randomization (MR) analysis.
Results: Compared to mild AP, patients with severe AP had higher gene expression of MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. GeneMANIA revealed 77.6% physical interactions among MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. Our results indicated that HLAP group had a more severe pancreatic injury, a stronger inflammatory response with higher serum levels of TNF-α, IL-6 and IL-1β in comparison with the AP group, which were significantly mitigated in HLAP-Pi group. Furthermore, SB 203580 inhibited increasing levels of malondialdehyde (MDA) in serum and of inducible nitric oxide synthase (iNOS), P38MAPK, p-P38MAPK and NF-κB p65 in pancreatic tissue as well as decreasing serum values of SOD and GSH-PX in HLAP group. MR analysis suggested that MAPK14 levels were negatively associated with the SOD levels, by using the inverse variance weighted (IVW) method (b=-0.193: se=0.225; P=1.03e-17). Reverse MR analysis indicated that SOD was negatively associated with the MAPK14 levels in the IVW analysis (b=-0.163: se=0.020; P=1.38e-15).
Conclusion: Interactions between P38MAPK and oxidative stress may play an important role in the pathogenesis of HLAP.
... also found that additional variables had an impact on AP development, but only to a lesser degree. [22] Mitochondrial dysfunction and Ca2+ signaling Cell damage in the body may occur via a common process known as Ca2+ overload. As part of its regular physiological function, cholecystokinin triggers the endoplasmic reticulum (ER) to release stored calcium via the InsP3 receptor and the ryanodine receptor pathways. ...