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).

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 IB- (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 ...
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... (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 ...
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... 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 ...
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... 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 ...
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... 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 ...
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... 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 ...
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... 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 ...
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... 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 ...

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... 12À14 This process, if uncontrolled, generates an overwhelmed amount of nonesterified fatty acids (NEFAs), which in turn aggravate the damage to pancreatic acinar cells and even lead to organ failure. 12,13,15 The liver serves as a metabolic hub responsible for maintaining the homeostasis of fatty acids, glucose, and amino acids. 16 Fatty acid b-oxidation (FAO) is a major catabolic process that degrades long-chain (LC) acyl-CoA to acetyl-CoA, 17 which then enters the tricarboxylic acid (TCA) cycle or ketogenesis process for energy production. ...
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... Fourth, this study focused only on the muscle quantity to explain the obesity paradox, excluding serologic tests such as C-reactive protein or albumin. Given that visceral fat composition is recently suggested to be associated with inflammatory response and explains the obesity paradox, 39 further research is demanded. Lastly, the lack of a validation sample is another limitation in this study. ...
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