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Effect of visceral fat composition on its lipolysis and associated inflammatory response. (A) Gross appearance of the FN in SFA-fed (top) and UFA-fed mice with pancreatitis. (B1) PNLIP, IKB-, and -tubulin (-Tub) amounts on Western blotting (B2) in the fat pads of SFA-or UFA-fed control (Con) mice or those with CER pancreatitis (CER). Cytokine mRNA levels in fat pads (C1) shown as an increase over control levels or serum levels of IL-6 (C2), MCP-1 (C3), or TNF- (C4) in control mice or those with CER pancreatitis after they had been fed with UFA-or SFA-enriched diets. Serum NEFA showing OA (D1), LA (D2), total serum UFA (C3), total serum NEFA (D4), PA (D5), palmitoleic acid (D6), total serum SFA (D7), and serum SFA as a percentage of total NEFA (D8) in control mice or those with CER pancreatitis after they had been fed with UFA-or SFA-enriched diets. Photo credit: Krutika Patel, Mayo Clinic, AZ.
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...
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Citations
... Substantially elevated serum FA levels have been observed in the AP population, and abnormal fluctuations in FA levels (such as those of AA and linoleic acid) have been reported to be correlated with the deterioration of AP [28]. A meta-analysis including 20 reports from 11 countries has revealed that UFAs derived from the lipolysis of unsaturated visceral triglycerides increased systemic injury and organ failure during pancreatitis [29]. In the present study, an increase in AA was observed. ...
Yiyi decoction is a Chinese herbal formula for the treatment of acute pancreatitis that has been used in clinical practice for decades. A previous study has suggested that resveratrol, emodin, rhein and their derivatives might be the potential pharmacodynamic components in Yiyi decoction, and researchers have proposed that resveratrol, emodin and rhein are candidate markers for quality control. The present study investigated the intervention effect of Yiyi decoction and its effective components on murine acute pancreatitis using metabolomic approach that integrated global and unique metabolic characteristics. First, serum metabolomics based on the platform of ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was performed to assess metabolic changes in experimental acute pancreatitis. Second, an in-depth analysis of bile acid metabolism was performed based on an in-house database. Finally, an integrated analysis of the intervention effect of Yiyi decoction and its effective components in response to these metabolic perturbations was performed. As a result, 39 potential biomarkers for the pathogenesis of acute pancreatitis, mainly phospholipids, fatty acids, bile acids and lipoylcarnitines, were screened and annotated. Integrated analysis revealed that the metabolic disorders in acute pancreatitis mice were reversed by Yiyi decoction primarily via regulating glycerophospholipid metabolism, bile acid biosynthesis, carnitine synthesis and fatty acid metabolism. Yiyi decoction components may effectively target the migratory metabolome. Histopathological and biochemical analyses suggested that Yiyi decoction maintained the gut barrier function and inhibited inflammatory cytokines, thus exert anti-acute pancreatitis effects. The present study utilized an approach that integrated global and unique metabolic characteristics to elucidate the underlying mechanisms of Chinese herbal formulas from a metabolomics perspective.
... TGs have three long chain (≥16 carbon length) fatty acids (i.e. TGFAs) covalently esterified to a glycerol backbone (23). The principal long chain NEFAs comprising the serum NEFA pool (25) are 1) stearic acid (S, C18:0), 2.) palmitic acid (P: C16:0), 3.) palmitoleic acid (PO; C16:1), 4.) oleic acid (O, C18:1), and 5.) linoleic acid (L: C18:2). ...
... Therefore, while L (C18:2) has the highest fidelity of lipolysis by pancreatic lipases, adding O (C18:1) and P (C16:0) incrementally decrease this fidelity. These results support the concept that double bonds (i.e., unsaturation) in long chain fatty acids increase their lipolysis from a TG, and saturation interferes with TG lipolysis (23). Overall our results show excessive generation of unsaturated NEFA from circulating triglyceride lipolysis may cause organ failure, and worsen HTG-AP severity. ...
... Figure 5 summarizes these findings. It shows that lipolysis during HTG-AP, preferentially generates unsaturated NEFAs, which injure cells and cause organ failure as previously shown (19) (22,23). These findings also agree with previous studies showing that unsaturation increases TG hydrolysis to NEFA by the pancreatic lipases released in AP (23), and that HTG-AP is detrimental irrespective of AP etiology (2,7,8). ...
... 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. ...
Acute pancreatitis (AP) has no targeted therapy. Previously, pancreatic cooling to 31°C–33°C and 24°C–27°C, respectively, ameliorated mild and severe AP in rats. Here, Yucatan pigs (40–50Kg) whose abdominal size and anatomy are like humans underwent pancreatic cooling. This was via a gastric cooling balloon placed endoscopically with catheters exteriorized on the abdominal wall. Laparoscopically placed wireless transmitters monitored pancreas tail, head, and urinary bladder temperatures. Controls included un-perfused water filled balloons, and sedation-only groups. Tap water perfusion (375 mL/min) over 1-month was well tolerated without sedation. Perfusion with ≤19°C water achieved pancreatic temperatures ≤32°C and perfusion at ≤10°C achieved ≤26°C in <90 min in sedated supine pigs, which normalized an hour after balloon evacuation. Bladder temperatures, behavioral, biochemical, hematological, and histological parameters were similar between groups. Therefore, rapid transgastric pancreatic cooling can be achieved safely in large animals with relevant anatomy like humans, warranting future clinical studies.
... 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.
