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Dietary and adipose fat composition and parameters of local, systemic severity of CER pancreatitis in UFA-and SFA-fed ob/ob mice. (A1) Table comparing the fatty acid composition of fat pad triglycerides (TG) and diets of mice given the SFA-and UFA-enriched diets. Body weights (A2), body fat (A3), and body fat as a percentage of body weight (A4) in the SFA-and UFA-fed mice. Serum amylase (B1) and lipase (B2) in control (CON) mice and after 24 hours of AP (CER). Local pancreatic injury seen histologically (C1) and quantified as acinar necrosis (C2) as a percentage of total parenchymal area and percentage of acinar necrosis adjacent to the FN (shown in yellow rectangles), termed as "% peri-fat acinar necrosis" (C3). Systemic injury measured as renal injury [TUNEL staining showing brown nuclei in (D1) and serum BUN in (D2)], lung TUNEL positivity highlighted with arrows in (D3), and shown as number per high-power field (HPF) in (D4), along with shock (as measured by a drop in carotid pulse distention) in (E1), serum calcium (E2), and survival curve (E3) of mice with CER AP. NS, not significant.
Source publication
Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context...
Contexts in source publication
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... averaged 45.5 ± 0.5 g in both groups. CER AP reduced survival to 10% in the UFA group by day 3 versus 90% in the SFA group (P < 0.02; fig. S6). We then simulated the lower cutoff BMI (≤25) associated with SAP in countries with a higher %UFA intake. AP was initiated in UFA-fed mice weighing 20 to 30% less and having 35 to 40% less adipose tissue (Fig. 2, A2 to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner UFA group. The SFA group has lesser pancreatic necrosis (5.8 ± 0.8 versus 16.8 ± 4.7%, P = 0.024; Fig. 2, C1 and C2) especially bordering FN, termed peri-fat acinar necrosis (2.7 ± 0.4 versus 6.9 ± 1.6%, P = 0.03; ...
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... a higher %UFA intake. AP was initiated in UFA-fed mice weighing 20 to 30% less and having 35 to 40% less adipose tissue (Fig. 2, A2 to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner UFA group. The SFA group has lesser pancreatic necrosis (5.8 ± 0.8 versus 16.8 ± 4.7%, P = 0.024; Fig. 2, C1 and C2) especially bordering FN, termed peri-fat acinar necrosis (2.7 ± 0.4 versus 6.9 ± 1.6%, P = 0.03; green outline, Fig. 2, C1 and C3). Consistent with SAP (53, 54), the UFA-fed mice had greater lung and renal tubular TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) positivity, ...
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... to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner UFA group. The SFA group has lesser pancreatic necrosis (5.8 ± 0.8 versus 16.8 ± 4.7%, P = 0.024; Fig. 2, C1 and C2) especially bordering FN, termed peri-fat acinar necrosis (2.7 ± 0.4 versus 6.9 ± 1.6%, P = 0.03; green outline, Fig. 2, C1 and C3). Consistent with SAP (53, 54), the UFA-fed mice had greater lung and renal tubular TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) positivity, higher serum blood urea nitrogen (BUN) levels (Fig. 2, D1 to D4), a greater decrease in carotid pulse distention (consistent with ...
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... transferase-mediated deoxyuridine triphosphate nick end labeling) positivity, higher serum blood urea nitrogen (BUN) levels (Fig. 2, D1 to D4), a greater decrease in carotid pulse distention (consistent with shock), and SAP-associated hypocalcemia (55, 56) (Fig. 2, E1 and E2), resulting in 20% survival (P < 0.02 versus 90% in the SFA group; Fig. 2E3). The findings of SAP were replicated in UFA-fed C57BL6 mice with diet-induced obesity (DIO), but not the normal chow-fed mice (30.8 ± 0.7 g), which had mild pancreatitis ( fig. S7, A to F) (27). However, we did not use DIO as the primary model since the time to weight gain (>5 months) was ...
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... UFA mice had a larger cytokine mRNA increase in the fat pads during AP and interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- (TNF-) proteins in the sera (Fig. 3, C1 to C4), which correlated with lower IB- (42 ± 15% of controls, P < 0.05) in the necrosed UFA fat pads (Fig. ...
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... (LA-OA-PA), and compared these to GTL (LA-LA-LA). Palmitate disproportionately reduced lipolysis over 15 min. For example, LLP generated <30% LA, and PLP generated <9% LA versus GTL (Fig. 5B1). Both linoleate (4.3 ± 1 M) and oleate (4.4 ± 1.2 M) generation were markedly reduced on LOP. This was paralleled by reductions in m and Cai increase (Fig. 5, B2 and ...
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... a distance of 4.04 Å between the hydroxyl group of Ser 152 and the carbonyl C atom of the triglyceride's glycerol backbone (Fig. 5D1). LLP docked with a GlideScore of −4.72 kcal/mol at a distance of 9.99 Å from Ser 152 , and LOP and GTP respectively produced GlideScores of −1.33 and −1.58 while being 12.42 and 11.98 Å from the catalytic serine (Fig. 5, D2 to D4). To verify the integrity of the docking simulation, the ligand present in the 1LPA crystal structure (61), dilauryl phosphatidyl choline (DLPC), was removed and then docked with the same induced fit docking protocol used for the three triglycerides. DLPC docked with a GlideScore of −7.46 ( fig. S14A) and at a distance of 3.59 Å ...
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... of visceral fat more prone to lipolysis (Figs. 2 and 3), generating higher concentrations of monomeric NEFA (Fig. 6), thus worsening outcomes in leaner populations (Fig. 1). The reverse holds true for SFAs, and this is relevant to studies from Western countries (72) that show AP severity to be independent of intra-abdominal fat amounts even when this fat is above the range in studies from Asian countries (71). ...
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... enantiopure form. While this remains beyond our scope, the previous findings that pancreatic lipase hydrolyzes triglyceride without any stereoselectivity for the sn-1 or sn-3 position (59) suggest that the interference by palmitate is independent of these locations on the glycerol backbone. Last, the mechanisms underlying the exothermic changes (Fig. 5, C2 and C3) following the initial interaction of PNLIP and triglycerides remain unclear. The relative magnitude of these, i.e., GTL > LLP > LOP, mirror the initial interaction. Previous studies suggest that this may be due to binding of the generated LA to aromatic residues on PNLIP and further increasing its activity ...
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... explore the impact of BMI on AP severity, we conducted a literature review by searching the PubMed database from inception to January 2017). The terms "BMI" or "obese" and "acute pancreatitis" as well as "severe" or "severity" were used. A total of 118 studies were retrieved, as shown ( fig. S2). Seventy-nine studies were excluded, as they were not related to the subject of this review, as were 12 studies that were reviews/meta-analyses/hypotheses. The remaining studies were extensively reviewed for eligibility criteria, which were as follows: (i) clear BMI cutoff to define obesity, (ii) clear report of the incidence of mild ...
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... was divided into MAP and SAP and then into those that were obese versus nonobese. In cases where this was not explicitly clear, the communicating author was contacted (30,45), and the numbers so provided were included in the study. Papers that did not have adequate data or for reasons mentioned in the last column of fig. S1 and detailed in fig. S2 were excluded from the meta-analysis (n = 7). When more than one BMI cutoff was mentioned, the BMI used was the one at which the SAP risk ...
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Citations
... older, those with preexisting organ dysfunction), with hypertriglyceridemia, and/or pancreatic lipase-dependent lipotoxicity. (53)(54)(55) In many cases, signs and symptoms of MODS and MOF are present at initial assessment due to patient delay in seeking medical attention for their conditions and/or systems associated delays. In contrast, others present early in the course before these signs and symptoms develop resulting in underestimation of the severity of the evolving clinical course since MODS and MOF may take up to 24 hours or longer to develop. ...
Acute pancreatitis (AP) is an inflammatory reaction of the pancreas caused by inappropriate trypsin activation and an injury / innate inflammatory response. The many etiologies and potentially life-threatening consequences of AP require that clinicians initiate prompt and individualized treatment upon diagnosis. Application of new advances in the management of AP are required at the point of care. To facilitate care, a group of clinical experts have developed a set of recommendations for the evaluation and management of AP during the first 24 hours based on current evidence and evolving concepts. Ten areas of care are addressed where expert recommendations may be useful: (1) physical examination, (2) laboratory tests, (3) diagnosis, (4) early treatment, (5) severity determination, (6) etiology-based management, (7) typical orders sets, (8) determining of appropriate level of care, (9) quality of care, and (10) quality improvement recommendations. Conclusion: These recommendations should become available as clinical decision support tools that are accessible at the point of care, in real time.
... The ACSL5 (Acyl-CoA synthetase long chain family member 5) found in this region prefers LCFA as a substrate for the formation of acyl-CoAs, which are then used to synthesize complex lipids or enter mitochondria for beta-oxidation [68]. Another candidate gene in this region is the pancreatic triglyceride lipase (PNLIP) gene, which encodes the lipolytic enzymes that mediate the digestion and absorption of dietary fat [69,70]. During pancreatitis in humans, PNLIP content increased in adipose tissue and entered visceral adipocytes, inhibiting mitochondrial complexes I and V through the production of long-chain NEFA by hydrolyzing adipose TAG [71]. ...
... Under a high-fat diet, MGAT2-lacking mice showed better glucose tolerance and protected organisms from hepatic steatosis [93]. The PNLIP and its family members (PNLIPRP1, PNLIPRP2, PNLIPRP3) are involved in the hydrolysis of TAG, particularly targeting unsaturated substrates [69]. This function of the PNLIP gene is concordant with the identification of a QTL for the SFA content in the genomic region where PNLIP is located. ...
Background
The composition and distribution of fatty acids (FA) are important factors determining the quality, flavor, and nutrient value of meat. In addition, FAs synthesized in the body participate in energy metabolism and are involved in different regulatory pathways in the form of signaling molecules or by acting as agonist or antagonist ligands of different nuclear receptors. Finally, synthesis and catabolism of FAs affect adaptive immunity by regulating lymphocyte metabolism. The present study performed genome-wide association studies using FA profiles of blood, liver, backfat and muscle from 432 commercial Duroc pigs.
Results
Twenty-five genomic regions located on 15 Sus scrofa chromosomes (SSC) were detected. Annotation of the quantitative trait locus (QTL) regions identified 49 lipid metabolism-related candidate genes. Among these QTLs, four were identified in more than one tissue. The ratio of C20:4 n -6/C20:3 n -6 was associated with the region on SSC2 at 7.56–14.26 Mb for backfat, liver, and muscle. Members of the fatty acid desaturase gene cluster ( FADS1 , FADS2 , and FADS3 ) are the most promising candidate genes in this region. Two QTL regions on SSC14 (103.81–115.64 Mb and 100.91–128.14 Mb) were identified for FA desaturation in backfat and muscle. In addition, two separate regions on SSC9 at 0 – 14.55 Mb and on SSC12 at 0–1.91 Mb were both associated with the same multiple FA traits for backfat, with candidate genes involved in de novo FA synthesis and triacylglycerol (TAG) metabolism, such as DGAT2 and FASN . The ratio C20:0/C18:0 was associated with the region on SSC5 at 64.84–78.32 Mb for backfat. Furthermore, the association of the C16:0 content with the region at 118.92–123.95 Mb on SSC4 was blood specific. Finally, candidate genes involved in de novo lipogenesis regulate T cell differentiation and promote the generation of palmitoleate, an adipokine that alleviates inflammation.
Conclusions
Several SNPs and candidate genes were associated with lipid metabolism in blood, liver, backfat, and muscle. These results contribute to elucidating the molecular mechanisms implicated in the determination of the FA profile in different pig tissues and can be useful in selection programs that aim to improve health and energy metabolism in pigs.
... 22 Additionally, cooling can slow the lipolytic lipotoxic pathways in severe pancreatitis. 2,4,5,23,24 No single drug therapy has been effective in treating established acute pancreatitis. For example, targeting serine proteases with gabexate mesylate, 25 reactive oxygen species (ROS) with allopurinol, 26 and platelet-activating factor with lexipafant, 27 showed no benefit in clinical trials. ...
... Besides, serum TG levels can also impact the severity and prognosis of HTG-AP, with elevated levels increasing the incidence of persistent organ failure (POF), local complications, and mortality [11,12]. Notably, TG is not inherently toxic, and studies have shown that unsaturated long-chain nonesterified fatty acids (NEFA) hydrolyzed from unsaturated fatty acids (UFA) in TG can lead to harmful signal propagation, lipotoxic inflammation, and organ failure (OF), which is the main factor in aggravating AP [13,14]. ...
Background: Acute biliary pancreatitis (ABP) is the most common type of acute pancreatitis. However, the effect of serum triglyceride (TG) levels on the severity of ABP remains unclear. The aim of this study was to assess the correlation between serum TG levels and the severity of ABP. Methods: Data from 526 ABP patients was analyzed in this study. The patients were divided into normal and elevated groups according to the TG level measured within 24 h after admission, and the elevated group was further divided into mild, moderate, and severe elevated groups. The demographic data and clinical outcomes of each group were compared. Results: Of the 526 ABP patients, 394 were in the normal TG group and 132 were in the elevated TG group (36 mild, 57 moderate, and 39 severe). The elevated group was younger (51.5 ± 12.9 vs. 58.9 ± 13.9), predominantly male (66.7% vs. 45.2%), had more history of diabetes (22.7% vs. 12.4%) and hyperlipidemia (19.7% vs. 0.8%), and developed systemic inflammatory response syndrome (SIRS) (25.8% vs. 15.5%), persistent organ failure (POF) (11.4% vs. 2.8%), and local complications (62.9% vs. 42.1%) more frequently compared to the normal group (P < 0.05). The incidence of SIRS, POF, acute peripancreatic fluid collection (APFC), and acute necrotic collection (ANC) increased with increasing TG levels (P trend < 0.05). In multivariate analysis, TG was independently associated with POF, APFC, and ANC in increments of 100 mg/dl (P < 0.05), and there was a linear relationship between TG levels and POF, APFC, and ANC (non-linear P > 0.05, P overall <0.05). In addition, nonalcoholic fatty liver disease is not a risk factor for POF, ANC, and APFC in ABP patients. Conclusions: Elevated serum TG levels were independently associated with more severe ABP. The incidence of POF, APFC, and ANC in ABP patients increased with the increase of TG levels, with a linear relationship.
... Although LC-UFAs are widely recognized for their anti-inflammatory effects, high concentrations of LC-UFAs induce the necrosis of PACs, which increases the release of cell contents via cell membrane rupture. This, in turn, contributes to an amplified inflammatory response and hastens the development of AP [5,8,9]. Furthermore, fatty acid metabolites, such as fatty acid chlorohydrin and fatty acid ethyl esters (FAEEs) are involved in damaging PACs [10,11]. ...
... Conversely, OA alleviated lipid toxicity [30,31]. However, the impact of OA on PACs, whether protective or detrimental, is concentration-dependent [8,9,32]. ...
Acute pancreatitis (AP) is an inflammatory disease characterized by localized pancreatic injury and a systemic inflammatory response. Fatty acids (FAs), produced during the breakdown of triglycerides (TGs) in blood and peripancreatic fat, escalate local pancreatic inflammation to a systemic level by damaging pancreatic acinar cells (PACs) and triggering M1 macrophage polarization. This paper provides a comprehensive analysis of lipases' roles in the onset and progression of AP, as well as the effects of long-chain fatty acids (LCFAs) on the function of pancreatic acinar cells (PACs). Abnormalities in the function of PACs include Ca²⁺ overload, premature trypsinogen activation, protein kinase C (PKC) expression, endoplasmic reticulum (ER) stress, and mitochondrial and autophagic dysfunction. The study highlights the contribution of long-chain saturated fatty acids (LC-SFAs), especially palmitic acid (PA), to M1 macrophage polarization through the activation of the NLRP3 inflammasome and the NF-κB pathway. Furthermore, we investigated lipid lowering therapy for AP. This review establishes a theoretical foundation for pro-inflammatory mechanisms associated with FAs in AP and facilitating drug development.
... 24 25 The BMI cut-off in our study was <25 kg/m 2 , which is lower than the 30 kg/m 2 cut-off in most Western countries, probably because of the higher intake of unsaturated fats in the Chinese population. 26 The TyG, based on fasting blood glucose and triglyceride levels, is extensively used as an important indicator of cardiovascular events and IR. [27][28][29] The above weight-related and TG-related parameters all had good predictive effects on NAFPD, with AUCs greater than 0.70. ...
Objectives
Triglyceride (TG), triglyceride-glucose index (TyG), body mass index (BMI), TyG-BMI and triglyceride to high-density lipoprotein ratio (TG/HDL) have been reported to be reliable predictors of non-alcoholic fatty liver disease. However, there are few studies on potential predictors of non-alcoholic fatty pancreas disease (NAFPD). Our aim was to evaluate these and other parameters for predicting NAFPD.
Design
Cross-sectional study design.
Setting
Physical examination centre of a tertiary hospital in China.
Participants
This study involved 1774 subjects who underwent physical examinations from January 2016 to September 2016.
Primary and secondary outcome measures
From each subject, data were collected for 13 basic physical examination and blood biochemical parameters: age, weight, height, BMI, TyG, TyG-BMI, high-density lipoprotein (HDL), low-density lipoprotein, total cholesterol, TG, fasting plasma glucose, TG/HDL and uric acid. NAFPD was diagnosed by abdominal ultrasonography. A logistic regression model with a restricted cubic spline was used to evaluate the relationship between each parameter and NAFPD. The receiver operating characteristic (ROC) curve was used to calculate the area under the curve for each parameter.
Results
HDL was negatively correlated with NAFPD, height was almost uncorrelated with NAFPD and the remaining 11 parameters were positively correlated with NAFPD. ROC curve showed that weight-related parameters (weight, BMI and TyG-BMI) and TG-related parameters (TyG, TG and TG/HDL) had high predictive values for the identification of NAFPD. The combinations of multiple parameters had a better prediction effect than a single parameter. All the predictive effects did not differ by sex.
Conclusions
Weight-related and TG-related parameters are good predictors of NAFPD in all populations. BMI showed the greatest predictive potential. Multiparameter combinations appear to be a good way to predict NAFPD.
... It has been shown that the adverse effects of obesity appear to be reduced in older populations [65]. Khatua et al. suggested that the different visceral triglyceride saturation status could have varying effects on AP severity, explaining the obesity paradox [66]. Based on the results of the subgroup analysis in this meta-analysis, it appears that the mean age of patients has an effect on adiposity factors and resultantly affects AP severity, which may provide a new thought for the obesity paradox. ...
Background
Severe acute pancreatitis (SAP) is a dangerous condition with a high mortality rate. Many studies have found an association between adipokines and the development of SAP, but the results are controversial. Therefore, we performed a meta-analysis of the association of inflammatory adipokines with SAP.
Methods
We screened PubMed, EMBASE, Web of Science and Cochrane Library for articles on adipokines and SAP published before July 20, 2023. The quality of the literature was assessed using QUADAS criteria. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated to assess the combined effect. Subgroup analysis, sensitivity analysis and publication bias tests were also performed on the information obtained.
Result
Fifteen eligible studies included 1332 patients with acute pancreatitis (AP). Pooled analysis showed that patients with SAP had significantly higher serum levels of resistin (SMD = 0.78, 95% CI:0.37 to 1.19, z = 3.75, P = 0.000). The difference in leptin and adiponectin levels between SAP and mild acute pancreatitis (MAP) patients were not significant (SMD = 0.30, 95% CI: -0.08 to 0.68, z = 1.53, P = 0.127 and SMD = 0.11, 95% CI: -0.17 to 0.40, z = 0.80, P = 0.425, respectively). In patients with SAP, visfatin levels were not significantly different from that in patients with MAP (SMD = 1.20, 95% CI: -0.48 to 2.88, z = 1.40, P = 0.162).
Conclusion
Elevated levels of resistin are associated with the development of SAP. Resistin may serve as biomarker for SAP and has promise as therapeutic target.
... Unsaturated fatty acids are particularly harmful and can cause mitochondrial dysfunction, calcium overload, and the generation of inflammatory mediators in pancreatic acinar cells. [98][99][100] Additionally, hypertriglyceridemia worsens outcomes in AP, regardless of the initial cause. [101] This effect appears to be increased in obese patients and mice, likely due to lipolysis of intrapancreatic fat. ...
... This generates high lipotoxic-free fatty acid levels that worsen inflammation and organ failure. [100] The findings provide a potential explanation for the "obesity paradox" in AP, where obesity sometimes seems protective. The results suggest dietary fat saturation, not just the amount of body fat, contributes to pancreatitis severity through effects on lipotoxicity. ...
Acute pancreatitis is a severe inflammatory disorder with limited treatment options. Improved understanding of disease mechanisms has led to new and potential therapies. Here we summarize what we view as some of the most promising new therapies for treating acute pancreatitis, emphasizing the rationale of specific treatments based on disease mechanisms. Targeted pharmacologic interventions are highlighted. We explore potential treatment benefits and risks concerning reducing acute injury, minimizing complications, and improving long-term outcomes. Mechanisms associated with acute pancreatitis initiation, perpetuation, and reconstitution are highlighted, along with potential therapeutic targets and how these relate to new treatments.
... It is known that FFAs are of two types based on the presence or absence of C-C double bonds: 1) saturated fatty acids (SFA) and 2) unsaturated fatty acids (UFA). Dietary unsaturated/saturated components determine the fatty acid composition in fat cell triglyceride, affecting AP severity [58]. Cellular excess long-chain SFA is considered to be associated with lipotoxicity [59]. ...
... Oleic acid has been found to be the most abundant FFA found in pancreatic necrotic collections [63]. UFA produce higher levels of FFA as they are more easily lipolysis by pancreatic lipase [57,58]. The better aqueous UFA stability helps them exist as monomers at higher concentrations than SFA, resulting in lipotoxic inflammation and organ failure [58,64]. ...
... UFA produce higher levels of FFA as they are more easily lipolysis by pancreatic lipase [57,58]. The better aqueous UFA stability helps them exist as monomers at higher concentrations than SFA, resulting in lipotoxic inflammation and organ failure [58,64]. notably, UFA caused a sudden release of intracellular calcium, inhibition of mitochondrial complexes I and V, upregulation of inflammatory mediators and acinar necrosis causes acute pancreatitis [65]. ...
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.
... Pancreatic lipases can induce the lipolysis of adipocyte triglycerides to non-esterified free fatty acids (NEFA). Unsaturated fatty acids (UFAs) induce acinar cell injury, promotes local pancreatic injury and mediates lipotoxicity as well as progression to multisystem organ failure [12][13][14][15]. Obesity results in a low-grade pro-inflammatory state, and more pro-inflammatory cytokines are activated in AP [16][17][18][19]. ...
Obese people with acute pancreatitis (AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which SAP occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with AP have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same-age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis, and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis in obese mice.