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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
... It is known that FFAs are of two types based on the presence or absence of C-C double bonds: 1) saturated fatty acids (SFA) and 2) unsaturated fatty acids (UFA). Dietary unsaturated/saturated components determine the fatty acid composition in fat cell triglyceride, affecting AP severity [58]. Cellular excess long-chain SFA is considered to be associated with lipotoxicity [59]. ...
... Oleic acid has been found to be the most abundant FFA found in pancreatic necrotic collections [63]. UFA produce higher levels of FFA as they are more easily lipolysis by pancreatic lipase [57,58]. The better aqueous UFA stability helps them exist as monomers at higher concentrations than SFA, resulting in lipotoxic inflammation and organ failure [58,64]. ...
... UFA produce higher levels of FFA as they are more easily lipolysis by pancreatic lipase [57,58]. The better aqueous UFA stability helps them exist as monomers at higher concentrations than SFA, resulting in lipotoxic inflammation and organ failure [58,64]. notably, UFA caused a sudden release of intracellular calcium, inhibition of mitochondrial complexes I and V, upregulation of inflammatory mediators and acinar necrosis causes acute pancreatitis [65]. ...
It is well known, that the inflammatory process that characterizes acute pancreatitis (AP) can lead to both pancreatic damage and systemic inflammatory response syndrome (SIRS). During the last 20 years, there has been a growing incidence of episodes of acute pancreatitis associated with hypertriglyceridaemia (HTAP). This review provides an overview of triglyceride metabolism and the potential mechanisms that may contribute to developing or exacerbating HTAP. The article comprehensively discusses the various pathological roles of free fatty acid, inflammatory response mechanisms, the involvement of microcirculation, serum calcium overload, oxidative stress and the endoplasmic reticulum, genetic polymorphism, and gut microbiota, which are known to trigger or escalate this condition. Future perspectives on HTAP appear promising, with ongoing research focused on developing more specific and effective treatment strategies.
... Pancreatic lipases can induce the lipolysis of adipocyte triglycerides to non-esterified free fatty acids (NEFA). Unsaturated fatty acids (UFAs) induce acinar cell injury, promotes local pancreatic injury and mediates lipotoxicity as well as progression to multisystem organ failure [12][13][14][15]. Obesity results in a low-grade pro-inflammatory state, and more pro-inflammatory cytokines are activated in AP [16][17][18][19]. ...
Obese people with acute pancreatitis (AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which SAP occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with AP have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same-age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis, and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis in obese mice.
... 31 Studies have highlighted stark racial differences in the epidemiology of AP as ethnic minorities usually tend to have a greater degree of severity of AP and are associated with an increased risk of adverse outcomes. 21,[32][33][34][35] These subset populations may have less access to education, less access to healthcare, and diminished healthcare coverage, which often leads to a delayed presentation, development of complications, and a more severe clinical course of the disease. 21 Literature reports that Black populations have 2-3 times greater risk of hospitalization secondary to AP compared with their White counterparts. ...
... 21,[32][33][34][35] These subset populations may have less access to education, less access to healthcare, and diminished healthcare coverage, which often leads to a delayed presentation, development of complications, and a more severe clinical course of the disease. 21 Literature reports that Black populations have 2-3 times greater risk of hospitalization secondary to AP compared with their White counterparts. [32][33][34] Blacks have also been noted to have higher rates of readmissions of AP after the index episode. ...
Objective:
To identify the influence of body mass index (BMI) on Acute Pancreatitis (AP) hospitalizations in the United States (US).
Methods:
The National Inpatient Sample was utilized to identify normal weight, overweight and obese AP hospitalizations in the US from 2016-2019 based on BMI. Hospitalization characteristics and outcomes were compared.
Results:
Between 2016-2019, there were 314,215 (74.7%) obese, 27,005 (6.4%) overweight and 79,380 (18.9%) normal weight AP hospitalizations. Obese AP hospitalizations were younger (51.5 vs 56.5 years, p < 0.0001) compared to the normal weight cohort. However, normal weight AP hospitalizations had a higher proportion of Blacks and Asians compared to the obese subgroup. We also noted a higher all-cause inpatient mortality for normal weight AP hospitalizations (3.4% vs 2.8% vs 1.8%, p < 0.0001) compared to the overweight and obese cohorts, respectively. Furthermore, normal weight AP hospitalizations had a higher proportion of patients with pancreatic pseudocyst formation and pancreatic necrosis compared to the overweight and obese cohorts. The mean length of stay (5.8 vs 8.2 days, p < 0.0001) and mean total healthcare costs ($66,742 vs $82,319, p < 0.0001) were lower for obese compared to normal weight AP hospitalizations.
Conclusions:
Normal weight AP hospitalizations had higher inpatient mortality and complications compared to obese hospitalizations.
... Hypertriglyceridemia is the third most common cause of AP [13], and clinically, triglyceride-related metabolites are positively associated with the severity of AP [14,15] and pancreatic injury [16]. Lipotoxicity affects not only the multisystem organ failure of AP [17] but also regeneration after AP [18], and lipid saturation is also associated with lipotoxic systemic inflammation [19]; therefore, it is important to identify the lipids involved in the development of AP. We previously reported obviously changed phosphoglycerides and polyunsaturated fatty acyls are probably going to play an important role in the pathogenesis of a cerulein-induced AP mouse model [20]. ...
... In the positive mode, we detected a total of 487 lipids belonging to 8 different lipid subclasses. These included 21 PE-Ps, 19 Figure 4A and Table S6). Figure 4B demonstrates that the analytical process for screening changed representative lipids related to the Orn-SAP procession in the serum. ...
The relationship between the type and intensities of lipids of blood and pancreas and the pathological changes in the pancreas during severe acute pancreatitis (SAP) remains unclear. In our study, we employed a rat model of SAP induced through intraperitoneal ornithine injections. We collected serum and pancreas samples at various time points (0–144 h) for histopathological and biochemical assessments, followed by lipidomic analyses using LC-MS/MS or in situ mass spectrometry imaging (MSI) To discern changes over time or at specific points, we employed time-course and univariate analyses for lipid screening, respectively. Our findings indicated that the peak inflammation in the Orn-SAP model occurred within the 24–30 h timeframe, with evident necrosis emerging from 24 h onwards, followed by regeneration starting at 48 h. Time-course analysis revealed an overall decrease in glycerophospholipids (PEs, PCs, LPEs, LPCs), while CEs exhibited an increase within the pancreas. Univariate analysis unveiled a significant reduction in serum TAGs containing 46–51 carbon atoms at 24 h, and CERs in the pancreas significantly increased at 30 h, compared with 0 h. Moreover, a substantial rise in TAGs containing 56–58 carbon atoms was observed at 144 h, both in serum and pancreas. MSI demonstrated the CERs containing saturated mono-acyl chains of 16 and 18 carbon atoms influenced pancreatic regeneration. Tracing the origin of FFAs hydrolyzed from pancreatic glycerophospholipids and serum TAGs during the early stages of inflammation, as well as FFAs utilized for CEs and CERs synthesis during the repair phase, may yield valuable strategies for diagnosing and managing SAP.
... 5,6 However, previous studies have generated conflicting results: some even suggested the "obesity paradox," implying that obesity has protective effects in severe AP, 7 while others found that obesity does not increase the risk of organ failure. 8 Results regarding the impact of alcoholic etiology on AP outcomes have similarly been mixed. 9 This heterogeneity is largely attributable to significant methodologic constraints that plague both prospective observational studies and retrospective cohort studies that use large administrative databases. ...
... This is the largest prospective observational study in AP that pro- Although obesity has emerged as an important prognostic factor in several acute inflammatory illnesses, including sepsis and COVID-19, 5,16 AP literature has shown mixed results on whether obesity increases the risk of MSOF. 8,11 Most studies analyzed BMI as a dichotomized variable, which simplifies the interpretation of results but also increases the vulnerability to potential confounders and bias. 15 found that the increased risk of death among obese COVID-19positive subjects was seen exclusively among male subjects. ...
Background:
Multisystem organ failure (MSOF) is the most important determinant of mortality in acute pancreatitis (AP). Obesity and alcoholic etiology have been examined as potential risk factors for MSOF, but prior studies have not adequately elucidated their independent effects on the risk of MSOF.
Objective:
We aimed to determine the adjusted effects of body mass index (BMI) and alcoholic etiology on the risk of MSOF in subjects with AP.
Methods:
A prospective observational study of 22 centers from 10 countries was conducted. Patients admitted to an APPRENTICE consortium center with AP between August 2015 and January 2018 were enrolled. Multivariable logistic regression was used to estimate the adjusted effects of BMI, etiology, and other relevant covariates on the risk of MSOF. Models were stratified by sex.
Results:
Among 1544 AP subjects, there was a sex-dependent association between BMI and the risk of MSOF. Increasing BMI was associated with increased odds of MSOF in males (OR 1.10, 95% confidence interval [CI] 1.04-1.15) but not in females (OR 0.98, 95% CI 0.90-1.1). Male subjects with AP, whose BMIs were 30-34 and >35 kg/m2 , had odds ratios of 3.78 (95% CI 1.62-8.83) and 3.44 (95% CI 1.08-9.99), respectively. In females, neither higher grades of obesity nor increasing age increased the risk of MSOF. Alcoholic etiology was independently associated with increased odds of MSOF compared with non-alcohol etiologies (OR 4.17, 95% CI 2.16-8.05).
Conclusion:
Patients with alcoholic etiology and obese men (but not women) are at substantially increased risk of MSOF in AP.
... explained the obesity paradox in their article by suggesting that different visceral triglyceride saturation status could have varying effects on AP severity [51]. According to the results of the subgroup analysis in this meta-analysis, mean age of patients appears to have 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 March 2, 2023. The quality of the literature was assessed using QUADAS criteria. Standardised 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 936 patients with acute pancreatitis (AP). Pooled analysis showed that patients with SAP had significantly higher levels of circulating resistin (SMD = 0.55, 95% CI:0.15 to 0.94, z = 2.70, P = 0.007). The difference in circulating leptin and adiponectin levels between SAP and MAP patients was not significant (SMD = 0.31, 95% CI: -0.11 to 0.73, z = 1.44, P = 0.149 and SMD = -0.07, 95% CI: -0.30 to 0.16, z = 0.57, P = 0.570). Subgroup analyses identified mean age of the patients as possible sources of circulating resistin level heterogeneity.
Conclusion Elevated levels of circulating resistin levels are associated with the development of SAP. Resistin may be potential biomarkers and therapeutic targets for SAP. However, the age of the patient may influence these results.
... Western blotting was also performed using standard methods. 23 After protein denaturation, 20 μg of extracted protein was fractionated on a 10% SDS-PAGE gel and then transferred to a polyvinylidene fluoride (PVDF) membrane with a 0.45-mm pore size (Millipore, MA, USA). The membranes were then blocked in 5% milk at room temperature for 1 h, washed by TBST (Beyotime, Jiangsu, China) and incubated overnight on a shaker at 4°C for the primary antibody. ...
Purpose:
Although paclitaxel is widely used in cancer treatment, severe side effects and drug resistance limit its clinical use. 10-gingerol (10-G) is a natural compound isolated from ginger, which displays anti-inflammatory, antioxidant, and antiproliferative properties. However, the chemotherapy-sensitization effect of 10-G on triple-negative breast cancer (TNBC) has not been fully clarified. This study is aimed at investigating the effect of 10-G on the paclitaxel sensitivity in TNBC, and its underlying mechanism.
Methods:
The study was determined through in vitro and in vivo experiments. Cell viability and proliferation were detected by cell counting kit 8 (CCK-8) and colony formation. To detect cell apoptosis, flow cytometry and TUNEL were used. The expression of proteins was detected by Western blotting and immunohistochemistry. The molecular docking and gene knockout were corroborated by interactions between 10-G and adrenoceptor Beta 2 (ADRB2). The body weight of mice, histopathology and organs (kidney and spleen) coefficients were used to monitor the drug toxicities.
Results:
In vitro, 10-G increased the sensitivity of TNBC cells to paclitaxel, and could synergistically promote the apoptosis of TNBC cells induced by paclitaxel. In combination with molecular docking and lentivirus knockdown studies, ADRB2 was identified as a 10-G binding protein. 10-G inhibited ADRB2 by binding to the active site of ADRB2. Knockdown of ADRB2 reduces the proliferation activity of TNBC cells but also attenuates the sensitizing effects of 10-G to paclitaxel. Western blotting and immunohistochemistry showed that 10-G played an anti-proliferation and chemotherapy-sensitizing role by inhibiting the ADRB2/ERK signal. Toxicity evaluation showed that 10-G would not increase hepatorenal toxicity with paclitaxel.
Conclusion:
This data suggests that 10-G may be used as a new chemotherapeutic synergist in combination with paclitaxel to enhance anticancer activity. The potential value of ADRB2 as a target for improving chemotherapy sensitivity was also emphasized.
... 129 This entry can result from the concurrent release of phospholipases and be exacerbated by FA-induced adipocyte damage. 129 The resulting interaction between lipase and TG can cause fat necrosis of the involved adipocytes [129][130][131][132] and adipocyte receptor-associated TG release. This release, which may be mediated via G-protein coupled protease-activated receptor 4, 133 is triggered proteolytically by trypsin. ...
... 137 Recently, it was demonstrated that the dietary unsaturated/saturated composition determines the FA composition in adipocyte TG, which in turn can influence AP severity. 131 Unsaturated long-chain FAs in a TG make it more prone to lipolysis by pancreatic lipase, whereas saturated long-chain FAs in a TG interfere with this interaction. 131 Therefore, an unsaturated TG may be hydrolyzed more and generate more NEFAs than a saturated TG. ...
... 131 Unsaturated long-chain FAs in a TG make it more prone to lipolysis by pancreatic lipase, whereas saturated long-chain FAs in a TG interfere with this interaction. 131 Therefore, an unsaturated TG may be hydrolyzed more and generate more NEFAs than a saturated TG. Moreover, unsaturated long-chain NEFAs are more aqueous stable than saturated ones. ...
Hypertriglyceridaemia (HTG) is a metabolic disorder, defined when serum or plasma triglyceride concentration (seTG) is >1.7 mM. HTG can be categorized as mild to very severe groups based on the seTG value. The risk of acute pancreatitis (AP), a serious disease with high mortality and without specific therapy, increases with the degree of HTG. Furthermore, even mild or moderate HTG aggravates AP initiated by other important aetiological factors, including alcohol or bile stone. This review briefly summarizes the pathophysiology of HTG, the epidemiology of HTG‐induced AP and the clinically observed effects of HTG on outcomes of AP. Our main focus is to discuss the pathophysiological mechanisms linking HTG to AP. HTG is accompanied by an increased serum fatty acid (FA) concentration, and experimental results have demonstrated that these FAs have the most prominent role in causing the consequences of HTG during AP. FAs inhibit mitochondrial complexes in pancreatic acinar cells, induce pathological elevation of intracellular Ca2+ concentration, cytokine release and tissue injury, and reduce the function of pancreatic ducts. Furthermore, high FA concentrations can induce respiratory, kidney, and cardiovascular failure in AP. All these effects may contribute to the observed increased AP severity and frequent organ failure in patients. Importantly, experimental results suggest that the reduction of FA production by lipase inhibitors can open up new therapeutic options of AP. Overall, investigating the pathophysiology of HTG‐induced AP or AP in the presence of HTG and determining possible treatments are needed.
... Unsaturated fatty acids (UFA) induces acinar cell injury, promotes local pancreatic injury and mediates lipotoxicity as well as progression to multisystem organ failure [13][14][15][16] . Obesity results in a low-grade proin ammatory state, and more pro-in ammatory cytokines are activated during AP [17][18][19][20] . ...
Obese people with acute pancreatitis(AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which severe acute pancreatitis occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with acute pancreatitis have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis (MAP) in obese mice.
... La señalización continúa e interfiere principalmente con el factor de transcripción lipogénico (PPAR ) y en la proteína que regula los esteroles (SREBP-Ic). Esto hace comprender cómo es que la leptina al incrementar la actividad del AMP-Kinasa (AMP-K) disminuye la activación de la expresión de las enzimas lipogénicas malonil CoA carboxilasa y sintetasa de los AGL "efecto antiestatóico", en otras palabras, bloquea la enzima que sintetiza triglicéridos y ácidos grasos 24 . Al ser disminuido el efecto de los AGL por la leptina, se incrementa la expresión de CoA oxidasa y Carnitil-palmitoil transferasa (CPT-1) enzimas clave en la adecuada oxidación de ácidos grasos en la matriz mitocondrial, lo que hace a la leptina una hormona liporeguladora 25 . ...
Resumen Introducción. La diabesidad es el concepto para describir la ocurrencia de la diabetes y la obesidad de forma simultánea. En el mundo, cada día aumentan las cifras de personas con esta condición y se espera un crecimiento aún más elevado para años futuros, lo cual puede ser catastrófico para la salud individual, salud pública, economía y sistemas sanitarios. Desarrollo. Para comprender el fenómeno de la diabesidad se deben analizar diferentes factores. En este ensayo se plantean dos teorías con las que se puede dar sustento al desarrollo del padecimiento: Teoría del gen ahorrador de energía y desarrollo de genes sociales en el medio obesogénico. Conclusión. La diabesidad es un fenómeno complejo, multi-etiológico, basado en la influencia de las condiciones fisiológicas individuales y las condiciones del contexto social. Palabras clave: obesidad, diabetes, determinantes sociales de la salud. Abstract Introduction. Diabesity is when both diabetes and obesity occur simultaneously. Around the world, the number of people with diabesity is rising every day, and an even steeper climb is expected in the future. This growth in diabesity could have a detrimental effect on both the economy as well as personal health, public health, and healthcare systems. To fully understand the diabesity phenomenon, different factors should be analyzed. In this thesis, two theories will be presented to explain how the disease is manifested: the energy efficiency gene theory, and the social genes theory which will delve into how such genes are developed in an obesogenic environment. Conclusion. Diabesity is a complex, multi-etiological phenomenon, that stems from individual physiological conditions and conditions in the social context.
