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Relationship of human SAP to cutoff BMI and composition of dietary fat intake. (A) Studies using a BMI cutoff of ≤25 are shown in pink, those associating SAP with a BMI of ≥30 are shown in gold, and studies showing a BMI of >30 was not associated with severe AP (SAP) are show shown in blue. The respective countries from which the study originated are shown in pink, green, and blue, with a checkered pattern for countries with studies showing different outcomes. Box plot comparing the per capita per year saturated fat (from dairy, cattle, and palm oil) consumption in countries with BMI cutoffs of >30 and those with ≤25 BMI (B) and %UFA in dietary fat intake (C). (D) Meta-analysis showing OR for SAP for studies using a BMI cutoff of ≤25 (pink background) and those using a BMI cutoff of >30 (blue-yellow background). The overall OR is shown at the bottom (orange background).
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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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... saturated fat intake is associated with SAP at a higher BMI As seen in Fig. 1A and fig. S1, 20 reports from 11 countries used a BMI cutoff of ≥30 to stratify SAP. Six of these (blue countries and text in table) reported no increased risk (2,3,(30)(31)(32)(33)(34), while the 14 (golden text and green countries) reported an increased risk of SAP at BMI of ≥30 (1,6,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Six reports used a ...
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... Six reports used a cut off BMI of 25 or 1 less (8,9,(45)(46)(47)(48)(49). Adult AP typically occurs after the third decade (50,51). Since the composition of visceral fat necrosed during AP may be influenced by the dietary fat composition over the preceding years (26), we analyzed dietary fat composition of different countries shown in Fig. 1A. The per capita fat consumption was calculated by averaging the yearly data (1970 to 2011) for each country. Countries with a BMI cutoff of ≥30 had higher per capita saturated fat consumption (Fig. 1B and fig. S1). While the amount of unsaturated fat consumption was the same ( fig. S3A), unsaturated fat comprised a higher percentage of ...
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... may be influenced by the dietary fat composition over the preceding years (26), we analyzed dietary fat composition of different countries shown in Fig. 1A. The per capita fat consumption was calculated by averaging the yearly data (1970 to 2011) for each country. Countries with a BMI cutoff of ≥30 had higher per capita saturated fat consumption (Fig. 1B and fig. S1). While the amount of unsaturated fat consumption was the same ( fig. S3A), unsaturated fat comprised a higher percentage of fat intake in the countries with reports having a cutoff BMI of ≤25 (pink countries; Fig. 1, A and C). Overall, there was a moderate correlation between the percentage of patients with SAP and the percentage of ...
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... (1970 to 2011) for each country. Countries with a BMI cutoff of ≥30 had higher per capita saturated fat consumption (Fig. 1B and fig. S1). While the amount of unsaturated fat consumption was the same ( fig. S3A), unsaturated fat comprised a higher percentage of fat intake in the countries with reports having a cutoff BMI of ≤25 (pink countries; Fig. 1, A and C). Overall, there was a moderate correlation between the percentage of patients with SAP and the percentage of unsaturated fat intake (fig. S3B). On meta-analysis (Fig. 1D), a significantly increased risk of severity was noted for cutoff BMIs of ≤25 [pink shade, odds ratio (OR) 2.8, CI 1.3 to P = 0.008] and also BMI of >30 ...
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... was the same ( fig. S3A), unsaturated fat comprised a higher percentage of fat intake in the countries with reports having a cutoff BMI of ≤25 (pink countries; Fig. 1, A and C). Overall, there was a moderate correlation between the percentage of patients with SAP and the percentage of unsaturated fat intake (fig. S3B). On meta-analysis (Fig. 1D), a significantly increased risk of severity was noted for cutoff BMIs of ≤25 [pink shade, odds ratio (OR) 2.8, CI 1.3 to P = 0.008] and also BMI of >30 (blue and greens, OR 2.7, CI 1.8 to 3.8, P < 0.001). Publication bias was not detected on the basis of a Funnel plot ( fig. S1C), an Egger's regression, or a Begg and Mazumdar rank ...
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... percentage of unsaturated fat intake (fig. S3B). On meta-analysis (Fig. 1D), a significantly increased risk of severity was noted for cutoff BMIs of ≤25 [pink shade, odds ratio (OR) 2.8, CI 1.3 to P = 0.008] and also BMI of >30 (blue and greens, OR 2.7, CI 1.8 to 3.8, P < 0.001). Publication bias was not detected on the basis of a Funnel plot ( fig. S1C), an Egger's regression, or a Begg and Mazumdar rank correlation. There were no differences in age, sex distribution, or etiology of AP between the two groups ( fig. S1). While the effect of genes and comorbidities on %SAP cannot be commented on in these data, meta-regression showed that %unsaturated fatty acid (UFA) was able to ...
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... ratio (OR) 2.8, CI 1.3 to P = 0.008] and also BMI of >30 (blue and greens, OR 2.7, CI 1.8 to 3.8, P < 0.001). Publication bias was not detected on the basis of a Funnel plot ( fig. S1C), an Egger's regression, or a Begg and Mazumdar rank correlation. There were no differences in age, sex distribution, or etiology of AP between the two groups ( fig. S1). While the effect of genes and comorbidities on %SAP cannot be commented on in these data, meta-regression showed that %unsaturated fatty acid (UFA) was able to explain 33% of the heterogeneity in the rate of SAP, and neither age, AP etiology, nor per capita gross domestic product (GDP) correlated with SAP. Furthermore, while per ...
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... FDA-recommended dietary fats (52) (e.g., cooking oils) and comprises a high proportion in pancreatic fat necrosis (FN) (5,6). Being essential, LA's concentrations in visceral fat parallel dietary intake (29). We thus formulated a diet enriched in LA (70% LA in a 45% fat diet) to represent high %UFA intake in dietary fat (red box in fig. S4A and Fig. 2A1, red columns) (26,52). Similarly, a diet enriched in saturated fat was formulated, which had palmitic acid (PA; C16:0, PA 68% of a 47% fat diet; fig. S4B, green rectangle) replicating the 65 to 70% saturation of dairy fat. These diets spanned the range of %UFA intake in humans (16% in Australia and 79% in Japan), as shown in fig. S3A. ...
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... to 70% saturation of dairy fat. These diets spanned the range of %UFA intake in humans (16% in Australia and 79% in Japan), as shown in fig. S3A. Mice fed these diets had a similar food intake (6.5 ± 1.4 g/day of UFA diet or 6.3 ± 0.5 g/day of SFA diet). This altered their visceral triglyceride composition, with LA and PA increasing to 40 to 45% (Fig. 2A1 and detailed in fig. S5) in the UFA-and SFA-fed groups, respectively. We previously showed that a normal chow diet with 5% fat diet (Purina 5053), which contains ≥70% UFA and <20% SFA 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 ...
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... 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; green outline, Fig. 2, C1 and C3). Consistent with SAP (53, 54), the UFA-fed mice had ...
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... 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 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 ...
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... 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 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 ...
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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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... NEFA mediates cytokine increase (7), we measured serum NEFA to understand the underlying mechanism. The UFA group with AP had higher serum NEFA increase, especially UFAs, including C18:1 (OA) and C18:2 (LA) (Fig. 3, D1 to D4). This pattern has been noted during SAP-induced organ failure (7,28,53,54) in both rodents (5,6,27) and humans (4). However, inexplicably, the increase in C18:1, C18:2, and C16:1 (Fig. 3, D1, D2, and D6) was muted in the SFA-fed mice, despite C18:1 being equal and C16:1 being higher in the fat pads of the SFA group (Fig. 2A1 and fig. ...
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... to understand the underlying mechanism. The UFA group with AP had higher serum NEFA increase, especially UFAs, including C18:1 (OA) and C18:2 (LA) (Fig. 3, D1 to D4). This pattern has been noted during SAP-induced organ failure (7,28,53,54) in both rodents (5,6,27) and humans (4). However, inexplicably, the increase in C18:1, C18:2, and C16:1 (Fig. 3, D1, D2, and D6) was muted in the SFA-fed mice, despite C18:1 being equal and C16:1 being higher in the fat pads of the SFA group (Fig. 2A1 and fig. S5). Similarly, C16:0 and SFA overall (Fig. 3, D5 and D7, and fig. S8B) increased more in the UFA group, despite the SFA group having more of these in the visceral triglyceride, serum at ...
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... C18:2 (LA) (Fig. 3, D1 to D4). This pattern has been noted during SAP-induced organ failure (7,28,53,54) in both rodents (5,6,27) and humans (4). However, inexplicably, the increase in C18:1, C18:2, and C16:1 (Fig. 3, D1, D2, and D6) was muted in the SFA-fed mice, despite C18:1 being equal and C16:1 being higher in the fat pads of the SFA group (Fig. 2A1 and fig. S5). Similarly, C16:0 and SFA overall (Fig. 3, D5 and D7, and fig. S8B) increased more in the UFA group, despite the SFA group having more of these in the visceral triglyceride, serum at baseline. The proportion of SFA in general went down with AP (Fig. 3D8). This generalized reduction in SFA release suggested that SFAs in triglyceride ...
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... ob/ob mice given UFA or SFA diets (Fig. 2, B1 and B2). The AP outcomes also paralleled the UFA and SFA groups (Figs. 2 and 3) with 0% survival in the GTL groups versus 80 to 90% in the GTP groups (P < 0.01; Fig. 4A3 and fig. S9A3). The GTL group had worse pancreatic necrosis (Fig. 4, B1 to B3, and fig. S9, B1 and B2), predominantly at the periphery of the lobules exposed to the ...
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... SFA groups (Figs. 2 and 3) with 0% survival in the GTL groups versus 80 to 90% in the GTP groups (P < 0.01; Fig. 4A3 and fig. S9A3). The GTL group had worse pancreatic necrosis (Fig. 4, B1 to B3, and fig. S9, B1 and B2), predominantly at the periphery of the lobules exposed to the lipolytically generated LA, resembling peri-fat acinar necrosis (Fig. 2, C1 to C3). The higher serum glycerol and corresponding NEFA in the GTL groups with AP (Fig. 4, C1 and C2, and fig. S9, C1 to C3) supported preferential unsaturated triglyceride lipolysis. Serum BUN elevations, renal tubular injury (Fig. 4, D1 to D4, and fig. S9, D1 and D2), lung injury (fig. S10, A and B), and profound hypotension noted ...
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... the periphery of the lobules exposed to the lipolytically generated LA, resembling peri-fat acinar necrosis (Fig. 2, C1 to C3). The higher serum glycerol and corresponding NEFA in the GTL groups with AP (Fig. 4, C1 and C2, and fig. S9, C1 to C3) supported preferential unsaturated triglyceride lipolysis. Serum BUN elevations, renal tubular injury (Fig. 4, D1 to D4, and fig. S9, D1 and D2), lung injury (fig. S10, A and B), and profound hypotension noted as shock (fig. S10C) were only noted in the GTL groups with AP. Consistent with the small adipose tissue mass and visceral FN in lean mice (fig. S11, A1 and A2), there was no increase in serum resistin (Fig. 4E1 and fig. S9E1) and little or ...
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... BUN elevations, renal tubular injury (Fig. 4, D1 to D4, and fig. S9, D1 and D2), lung injury (fig. S10, A and B), and profound hypotension noted as shock (fig. S10C) were only noted in the GTL groups with AP. Consistent with the small adipose tissue mass and visceral FN in lean mice (fig. S11, A1 and A2), there was no increase in serum resistin (Fig. 4E1 and fig. S9E1) and little or no increase in serum lactate dehydrogenase (LDH) (fig. S11, B and E). However, consistent with NEFA-driven inflammation (7), serum IL-6, TNF-, and MCP-1 were higher in both AP models with GTL (Fig. 4, E2 to E4, and fig. S9, E2 to E4), perhaps due to the systemic lipotoxicity of LA noted as higher serum ...
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... renal tubular injury (Fig. 4, D1 to D4, and fig. S9, D1 and D2), lung injury (fig. S10, A and B), and profound hypotension noted as shock (fig. S10C) were only noted in the GTL groups with AP. Consistent with the small adipose tissue mass and visceral FN in lean mice (fig. S11, A1 and A2), there was no increase in serum resistin (Fig. 4E1 and fig. S9E1) and little or no increase in serum lactate dehydrogenase (LDH) (fig. S11, B and E). However, consistent with NEFA-driven inflammation (7), serum IL-6, TNF-, and MCP-1 were higher in both AP models with GTL (Fig. 4, E2 to E4, and fig. S9, E2 to E4), perhaps due to the systemic lipotoxicity of LA noted as higher serum damage-associated ...
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... (7), serum IL-6, TNF-, and MCP-1 were higher in both AP models with GTL (Fig. 4, E2 to E4, and fig. S9, E2 to E4), perhaps due to the systemic lipotoxicity of LA noted as higher serum damage-associated molecular patterns (DAMPs), i.e., doublestranded DNA (dsDNA) and histone-complexed DNA fragments in the GTL groups with pancreatitis ( fig. S11, C, D, F, and G). These findings suggested that unsaturated visceral triglyceride is hydrolyzed more than saturated triglyceride and worsens systemic inflammation and organ failure, consistent with what we note epidemiologically ( Fig. 1). We thus went on to study the mechanistic basis of this in more ...
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... i.e., doublestranded DNA (dsDNA) and histone-complexed DNA fragments in the GTL groups with pancreatitis ( fig. S11, C, D, F, and G). These findings suggested that unsaturated visceral triglyceride is hydrolyzed more than saturated triglyceride and worsens systemic inflammation and organ failure, consistent with what we note epidemiologically ( Fig. 1). We thus went on to study the mechanistic basis of this in more ...
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... (LLP) (LA-LA-PA), 1,3-dipalmitoyl-2-linoleoylglycerol (PLP) (PA-LA-PA), and 1-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (LOP) (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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... then studied the interaction and hydrolysis of GTL, LLP, and LOP focusing solely on triglyceride hydrolysis by human PNLIP in phosphate-buffered saline (PBS; pH 7.4, 37°C, 150 mM Na). The hydrolysis, i.e., GTL > LLP > LOP, paralleled those in the acinar cell media (Fig. 5C1). We thus studied their interaction with PNLIP using isothermal titration calorimetry ...
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... single injection of human PNLIP (0.7 nmol/s) into a stable, sonicated, stirred, and 100 M suspension of these triglycerides in PBS (at 300 s; fig. S13A) caused an endothermic interaction with a magnitude paralleling lipolysis, i.e., GTL > LLP > LOP, the enthalpy of which paralleled the raw heat data ( To verify the experimental results in an independent unbiased manner, we undertook docking simulations using the open lid conformation of the human PNLIP-procolipase complex (1LPA) (61) ...
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... produced. Orlistat docked with a distance of 3.74 Å between the catalytic serine and the -lactone ring that inhibits PNLIP hydrolysis. The induced fit protocol docked GTL into the 1LPA LBD with a GlideScore of −7.16 and with 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), ...
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... 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 from the hydroxyl group of the catalytic serine, which is 0.39 Å from its location in the crystal structure (3.20 Å). The resolution of 1LPA is 3.04 Å, so the variance seen is within the margin of error. DLPC inhibited the lipolysis of GTL added simultaneously in a dose-dependent manner ( fig. S14B). This ...
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... of −7.46 ( fig. S14A) and at a distance of 3.59 Å from the hydroxyl group of the catalytic serine, which is 0.39 Å from its location in the crystal structure (3.20 Å). The resolution of 1LPA is 3.04 Å, so the variance seen is within the margin of error. DLPC inhibited the lipolysis of GTL added simultaneously in a dose-dependent manner ( fig. S14B). This inhibition by DLPC, along with the redocking closely recapitulating the crystallographic findings, thus validates the docking simulation. Overall, these studies show that long-chain SFAs like palmitate make a triglyceride's interaction with PNLIP structurally and energetically unfavorable, thus reducing its hydrolysis. We lastly ...
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... while the PA group had no adverse outcome over 3 days. Serum NEFA (which are predominantly albumin bound) and unbound NEFA (uNEFA; Fig. 6, C and D) increased significantly only in the LA and OA groups, along with levels of the DAMP and dsDNA (Fig. 6E) and a drop in serum albumin consistent with the hypoalbuminemia noted during experimental ( fig. S15, A to C) and clinical SAP (55). This suggested that, unlike PA, both LA and OA with high uNEFA may directly injure cells, triggering DAMP release and downstream inflammation. This would also be consistent with the in vivo AP models (Figs. 3 and 4 and figs. S9 and S11, B to G) where higher NEFA were associated with worse ...
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... thus compared the ability of the most prevalent long-chain NEFA (C18:2, C18:1, and C16:0; Fig. 6, F1 to F3) to exist in a nonmicellar monomeric form in aqueous media. On ITC at 37°C, we noted the critical micellar concentration (CMC) and therefore the aqueous monomeric NEFA concentrations to increase with the number of double bonds (Fig. 6, F1 to F3). The CMCs of PA (C16:0), OA (C18:1), and LA (C18:2) were respectively <8, ≈40, and ≈160 M, ...
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... thus compared the ability of the most prevalent long-chain NEFA (C18:2, C18:1, and C16:0; Fig. 6, F1 to F3) to exist in a nonmicellar monomeric form in aqueous media. On ITC at 37°C, we noted the critical micellar concentration (CMC) and therefore the aqueous monomeric NEFA concentrations to increase with the number of double bonds (Fig. 6, F1 to F3). The CMCs of PA (C16:0), OA (C18:1), and LA (C18:2) were respectively <8, ≈40, and ≈160 M, which paralleled the uNEFA levels in vivo (Fig. 6D). The calorimetric results were then validated using ultracentrifugation. Both of these methods could be performed at room temperature (23°C; fig. S16) and showed that the nonmicellar NEFA ...
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... to increase with the number of double bonds (Fig. 6, F1 to F3). The CMCs of PA (C16:0), OA (C18:1), and LA (C18:2) were respectively <8, ≈40, and ≈160 M, which paralleled the uNEFA levels in vivo (Fig. 6D). The calorimetric results were then validated using ultracentrifugation. Both of these methods could be performed at room temperature (23°C; fig. S16) and showed that the nonmicellar NEFA concentrations in the infranatents of 500 M NEFA in PBS (pH 7.4), spun at 10 5 g for 1 hour ( fig. S16, A and B), were similar to the CMCs on calorimetry (fig. S16, C and D) and those shown previously using diphenyl hexatriene fluorescence spectroscopy (65). Thus, the CMC noted on calorimetrically ...
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... and ≈160 M, which paralleled the uNEFA levels in vivo (Fig. 6D). The calorimetric results were then validated using ultracentrifugation. Both of these methods could be performed at room temperature (23°C; fig. S16) and showed that the nonmicellar NEFA concentrations in the infranatents of 500 M NEFA in PBS (pH 7.4), spun at 10 5 g for 1 hour ( fig. S16, A and B), were similar to the CMCs on calorimetry (fig. S16, C and D) and those shown previously using diphenyl hexatriene fluorescence spectroscopy (65). Thus, the CMC noted on calorimetrically at 37°C (Fig. 6, F1 to F3) are ...
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... and showed that the nonmicellar NEFA concentrations in the infranatents of 500 M NEFA in PBS (pH 7.4), spun at 10 5 g for 1 hour ( fig. S16, A and B), were similar to the CMCs on calorimetry (fig. S16, C and D) and those shown previously using diphenyl hexatriene fluorescence spectroscopy (65). Thus, the CMC noted on calorimetrically at 37°C (Fig. 6, F1 to F3) are ...
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... 60 s after the addition of LA or OA to acini (Fig. 6J) or human embryonic kidney (HEK) 293 cells (Fig. 6K) to represent the pancreatic and kidney injury in vivo (Fig. 4, D1 to D4, and fig. S9, D1 and D2). Consistent with OA's CMC (≈40 M; Fig. 6F3), m increased over baseline at 50 M OA (*) and then plateaued (Fig. 6, J and K). Similarly, LA's m increased till 100 M and ceased at 200 M, consistent with its CMC of ≈160 M. While LA's m equaled OA's at 50 M, it was more than OA's (#) at concentrations of ≥100 M. LA ...
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... increased over baseline at 50 M OA (*) and then plateaued (Fig. 6, J and K). Similarly, LA's m increased till 100 M and ceased at 200 M, consistent with its CMC of ≈160 M. While LA's m equaled OA's at 50 M, it was more than OA's (#) at concentrations of ≥100 M. LA and OA (60 M), unlike PA, also reduced endothelial barrier integrity ( fig. S15, D and E), potentially explaining the hypotension (Fig. 2E1 and fig. S10C) hypothesized to be from vascular leak during SAP (66), along with explaining the hypoalbuminemia ( fig. S15, A to C) (55) in severe AP, and the uNEFA increase noted (Fig. 6D). Overall, these studies cumulatively validate that double bonds increase monomeric long-chain ...
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... (Fig. 6, J and K). Similarly, LA's m increased till 100 M and ceased at 200 M, consistent with its CMC of ≈160 M. While LA's m equaled OA's at 50 M, it was more than OA's (#) at concentrations of ≥100 M. LA and OA (60 M), unlike PA, also reduced endothelial barrier integrity ( fig. S15, D and E), potentially explaining the hypotension (Fig. 2E1 and fig. S10C) hypothesized to be from vascular leak during SAP (66), along with explaining the hypoalbuminemia ( fig. S15, A to C) (55) in severe AP, and the uNEFA increase noted (Fig. 6D). Overall, these studies cumulatively validate that double bonds increase monomeric long-chain NEFA concentrations and signaling in an aqueous environment, thus ...
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... LA's m equaled OA's at 50 M, it was more than OA's (#) at concentrations of ≥100 M. LA and OA (60 M), unlike PA, also reduced endothelial barrier integrity ( fig. S15, D and E), potentially explaining the hypotension (Fig. 2E1 and fig. S10C) hypothesized to be from vascular leak during SAP (66), along with explaining the hypoalbuminemia ( fig. S15, A to C) (55) in severe AP, and the uNEFA increase noted (Fig. 6D). Overall, these studies cumulatively validate that double bonds increase monomeric long-chain NEFA concentrations and signaling in an aqueous environment, thus enhancing their ...
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... note that the obesity paradox in pancreatitis (10) holds true when the data are grouped and analyzed by BMIs using the World Health Organization (WHO) cutoffs (67) relevant to the countries from which the study originated (Fig. 1), including those that use BMI cutoffs of ≤25, which have a lower SFA and higher %UFA consumption in diet (Fig. 1, B and C). Socioeconomic and quality-ofcare issues, age, sex, and etiology of AP are unlikely to have influenced our findings since the rate of SAP and mortality were the same in the >30 versus ≤25 BMI cutoff groups. We note ...
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... note that the obesity paradox in pancreatitis (10) holds true when the data are grouped and analyzed by BMIs using the World Health Organization (WHO) cutoffs (67) relevant to the countries from which the study originated (Fig. 1), including those that use BMI cutoffs of ≤25, which have a lower SFA and higher %UFA consumption in diet (Fig. 1, B and C). Socioeconomic and quality-ofcare issues, age, sex, and etiology of AP are unlikely to have influenced our findings since the rate of SAP and mortality were the same in the >30 versus ≤25 BMI cutoff groups. We note that the SAP rates and %UFA intake have a moderate correlation ( fig. S3B), and on meta-regression, %UFA intake explains ...
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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). This is exemplified by the six studies reporting a BMI of >30 to not be associated with severe ...
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... 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). This is exemplified by the six studies reporting a BMI of >30 to not be associated with severe AP-all of which came from countries with <40% UFA as dietary intake (Fig. ...
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... (22,24), perhaps support the general relevance of dietary and visceral fat unsaturation in causing the obesity paradox (11)(12)(13)(14)(15). A palmitate-enriched diet in ob/ob mice helped avoid the confounding effects of maldigestion of a dietary saturated triglyceride by pancreatic lipases, which we note as reduced lipolysis of GTP, LLP, and PLP (Fig. 5, A2 and B1). We used PNLIP since recent studies show that adipocyte triglyceride lipase, PNLIPRP2, and carboxyl ester lipase are unlikely to mediate lipotoxic systemic inflammation (7,53). Moreover, the similar lipolysis pattern in acinar media, which contains all three lipases (Fig. 5, A1 to A4 and B1 to B3) and PNLIP (Fig. 5, C1 to C3), lends ...
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... which we note as reduced lipolysis of GTP, LLP, and PLP (Fig. 5, A2 and B1). We used PNLIP since recent studies show that adipocyte triglyceride lipase, PNLIPRP2, and carboxyl ester lipase are unlikely to mediate lipotoxic systemic inflammation (7,53). Moreover, the similar lipolysis pattern in acinar media, which contains all three lipases (Fig. 5, A1 to A4 and B1 to B3) and PNLIP (Fig. 5, C1 to C3), lends credence of the concept to other ...
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... GTP, LLP, and PLP (Fig. 5, A2 and B1). We used PNLIP since recent studies show that adipocyte triglyceride lipase, PNLIPRP2, and carboxyl ester lipase are unlikely to mediate lipotoxic systemic inflammation (7,53). Moreover, the similar lipolysis pattern in acinar media, which contains all three lipases (Fig. 5, A1 to A4 and B1 to B3) and PNLIP (Fig. 5, C1 to C3), lends credence of the concept to other ...
Context 47
... (coenzyme A) desaturase-1(SCD-1) (73) is likely responsible for converting the dietary palmitate (C16:0) to palmitoleate (C16:1), which comprised 17% of the visceral triglyceride of SFA mice (Fig. 2A1 and fig. S5), despite palmitoleate being absent in the diet. SCD-1 is highly expressed in adipose tissue and can put a double bond in stearoyl-CoA or palmitoyl-CoA, thus forming oleate (C18:1) and palmitoleate from the palmitate in the diet. This may also explain the similar amounts of C18:1 noted in the visceral triglyceride of the UFA-and ...
Context 48
... reviewed for eligibility criteria, which were as follows: (i) clear BMI cutoff to define obesity, (ii) clear report of the incidence of mild AP (MAP) and SAP in obese versus nonobese groups, and (iii) clear and satisfactory definitions of MAP and SAP. Twenty-seven studies met our eligibility criteria and were therefore included in this review ( fig. S1). These are shown in different colors in Fig. 1A for descriptive purposes. The studies were then categorized into those using a BMI of 30 as a cutoff (n = 20, the one with a cutoff of >29 was included here) and those that used a cutoff BMI of ≤25 (n = 7; with text and country in pink) to define obesity's association with SAP. The ...
Context 49
... follows: (i) clear BMI cutoff to define obesity, (ii) clear report of the incidence of mild AP (MAP) and SAP in obese versus nonobese groups, and (iii) clear and satisfactory definitions of MAP and SAP. Twenty-seven studies met our eligibility criteria and were therefore included in this review ( fig. S1). These are shown in different colors in Fig. 1A for descriptive purposes. The studies were then categorized into those using a BMI of 30 as a cutoff (n = 20, the one with a cutoff of >29 was included here) and those that used a cutoff BMI of ≤25 (n = 7; with text and country in pink) to define obesity's association with SAP. The dietary fat consumption in the countries from which ...
Context 50
... those using a BMI of 30 as a cutoff (n = 20, the one with a cutoff of >29 was included here) and those that used a cutoff BMI of ≤25 (n = 7; with text and country in pink) to define obesity's association with SAP. The dietary fat consumption in the countries from which these papers originated was then extracted as described below and compared ( fig. S1). The incidence of MAP and SAP in both obese and nonobese patients was extracted for the purpose of meta-analysis. Total number of patients 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 ...
Context 51
... Total number of patients 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 ...
Context 52
... for fish) unless the food source was directly fat (e.g., cream, butter, ghee, cheese, vegetable oil, or palm oil). Data from the country from which each paper originated were included in the categories "BMI >30 not related to SAP," "BMI >30 associated with SAP," and cutoff "BMI ≤25" (shown as blue, green with golden text or symbols, and pink in Fig. 1, respectively). Each country was represented once in the category for a contributed paper (shown in Fig. 1, B and C). Comparisons were done by grouping the BMI of >30 not related to SAP and BMI of >30 associated with SAP into a grouped BMI of >30 category and by comparing this to the BMI of ≤25 category using a Mann-Whitney test. P < 0.05 was ...
Context 53
... oil). Data from the country from which each paper originated were included in the categories "BMI >30 not related to SAP," "BMI >30 associated with SAP," and cutoff "BMI ≤25" (shown as blue, green with golden text or symbols, and pink in Fig. 1, respectively). Each country was represented once in the category for a contributed paper (shown in Fig. 1, B and C). Comparisons were done by grouping the BMI of >30 not related to SAP and BMI of >30 associated with SAP into a grouped BMI of >30 category and by comparing this to the BMI of ≤25 category using a Mann-Whitney test. P < 0.05 was regarded as ...
Similar publications
Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese...
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.
