Dietary and adipose fat composition and parameters of local, systemic severity of CER pancreatitis in UFA-and SFA-fed ob/ob mice. (A1) Table comparing the fatty acid composition of fat pad triglycerides (TG) and diets of mice given the SFA-and UFA-enriched diets. Body weights (A2), body fat (A3), and body fat as a percentage of body weight (A4) in the SFA-and UFA-fed mice. Serum amylase (B1) and lipase (B2) in control (CON) mice and after 24 hours of AP (CER). Local pancreatic injury seen histologically (C1) and quantified as acinar necrosis (C2) as a percentage of total parenchymal area and percentage of acinar necrosis adjacent to the FN (shown in yellow rectangles), termed as "% peri-fat acinar necrosis" (C3). Systemic injury measured as renal injury [TUNEL staining showing brown nuclei in (D1) and serum BUN in (D2)], lung TUNEL positivity highlighted with arrows in (D3), and shown as number per high-power field (HPF) in (D4), along with shock (as measured by a drop in carotid pulse distention) in (E1), serum calcium (E2), and survival curve (E3) of mice with CER AP. NS, not significant.

Dietary and adipose fat composition and parameters of local, systemic severity of CER pancreatitis in UFA-and SFA-fed ob/ob mice. (A1) Table comparing the fatty acid composition of fat pad triglycerides (TG) and diets of mice given the SFA-and UFA-enriched diets. Body weights (A2), body fat (A3), and body fat as a percentage of body weight (A4) in the SFA-and UFA-fed mice. Serum amylase (B1) and lipase (B2) in control (CON) mice and after 24 hours of AP (CER). Local pancreatic injury seen histologically (C1) and quantified as acinar necrosis (C2) as a percentage of total parenchymal area and percentage of acinar necrosis adjacent to the FN (shown in yellow rectangles), termed as "% peri-fat acinar necrosis" (C3). Systemic injury measured as renal injury [TUNEL staining showing brown nuclei in (D1) and serum BUN in (D2)], lung TUNEL positivity highlighted with arrows in (D3), and shown as number per high-power field (HPF) in (D4), along with shock (as measured by a drop in carotid pulse distention) in (E1), serum calcium (E2), and survival curve (E3) of mice with CER AP. NS, not significant.

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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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... averaged 45.5 ± 0.5 g in both groups. CER AP reduced survival to 10% in the UFA group by day 3 versus 90% in the SFA group (P < 0.02; fig. S6). We then simulated the lower cutoff BMI (≤25) associated with SAP in countries with a higher %UFA intake. AP was initiated in UFA-fed mice weighing 20 to 30% less and having 35 to 40% less adipose tissue (Fig. 2, A2 to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner UFA group. The SFA group has lesser pancreatic necrosis (5.8 ± 0.8 versus 16.8 ± 4.7%, P = 0.024; Fig. 2, C1 and C2) especially bordering FN, termed peri-fat acinar necrosis (2.7 ± 0.4 versus 6.9 ± 1.6%, P = 0.03; ...
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... a higher %UFA intake. AP was initiated in UFA-fed mice weighing 20 to 30% less and having 35 to 40% less adipose tissue (Fig. 2, A2 to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner UFA group. The SFA group has lesser pancreatic necrosis (5.8 ± 0.8 versus 16.8 ± 4.7%, P = 0.024; Fig. 2, C1 and C2) especially bordering FN, termed peri-fat acinar necrosis (2.7 ± 0.4 versus 6.9 ± 1.6%, P = 0.03; green outline, Fig. 2, C1 and C3). Consistent with SAP (53, 54), the UFA-fed mice had greater lung and renal tubular TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) positivity, ...
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... to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner UFA group. The SFA group has lesser pancreatic necrosis (5.8 ± 0.8 versus 16.8 ± 4.7%, P = 0.024; Fig. 2, C1 and C2) especially bordering FN, termed peri-fat acinar necrosis (2.7 ± 0.4 versus 6.9 ± 1.6%, P = 0.03; green outline, Fig. 2, C1 and C3). Consistent with SAP (53, 54), the UFA-fed mice had greater lung and renal tubular TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) positivity, higher serum blood urea nitrogen (BUN) levels (Fig. 2, D1 to D4), a greater decrease in carotid pulse distention (consistent with ...
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... transferase-mediated deoxyuridine triphosphate nick end labeling) positivity, higher serum blood urea nitrogen (BUN) levels (Fig. 2, D1 to D4), a greater decrease in carotid pulse distention (consistent with shock), and SAP-associated hypocalcemia (55, 56) (Fig. 2, E1 and E2), resulting in 20% survival (P < 0.02 versus 90% in the SFA group; Fig. 2E3). The findings of SAP were replicated in UFA-fed C57BL6 mice with diet-induced obesity (DIO), but not the normal chow-fed mice (30.8 ± 0.7 g), which had mild pancreatitis ( fig. S7, A to F) (27). However, we did not use DIO as the primary model since the time to weight gain (>5 months) was ...
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... UFA mice had a larger cytokine mRNA increase in the fat pads during AP and interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- (TNF-) proteins in the sera (Fig. 3, C1 to C4), which correlated with lower IB- (42 ± 15% of controls, P < 0.05) in the necrosed UFA fat pads (Fig. ...
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... (LA-OA-PA), and compared these to GTL (LA-LA-LA). Palmitate disproportionately reduced lipolysis over 15 min. For example, LLP generated <30% LA, and PLP generated <9% LA versus GTL (Fig. 5B1). Both linoleate (4.3 ± 1 M) and oleate (4.4 ± 1.2 M) generation were markedly reduced on LOP. This was paralleled by reductions in m and Cai increase (Fig. 5, B2 and ...
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... a distance of 4.04 Å between the hydroxyl group of Ser 152 and the carbonyl C atom of the triglyceride's glycerol backbone (Fig. 5D1). LLP docked with a GlideScore of −4.72 kcal/mol at a distance of 9.99 Å from Ser 152 , and LOP and GTP respectively produced GlideScores of −1.33 and −1.58 while being 12.42 and 11.98 Å from the catalytic serine (Fig. 5, D2 to D4). To verify the integrity of the docking simulation, the ligand present in the 1LPA crystal structure (61), dilauryl phosphatidyl choline (DLPC), was removed and then docked with the same induced fit docking protocol used for the three triglycerides. DLPC docked with a GlideScore of −7.46 ( fig. S14A) and at a distance of 3.59 Å ...
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... of visceral fat more prone to lipolysis (Figs. 2 and 3), generating higher concentrations of monomeric NEFA (Fig. 6), thus worsening outcomes in leaner populations (Fig. 1). The reverse holds true for SFAs, and this is relevant to studies from Western countries (72) that show AP severity to be independent of intra-abdominal fat amounts even when this fat is above the range in studies from Asian countries (71). ...
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... enantiopure form. While this remains beyond our scope, the previous findings that pancreatic lipase hydrolyzes triglyceride without any stereoselectivity for the sn-1 or sn-3 position (59) suggest that the interference by palmitate is independent of these locations on the glycerol backbone. Last, the mechanisms underlying the exothermic changes (Fig. 5, C2 and C3) following the initial interaction of PNLIP and triglycerides remain unclear. The relative magnitude of these, i.e., GTL > LLP > LOP, mirror the initial interaction. Previous studies suggest that this may be due to binding of the generated LA to aromatic residues on PNLIP and further increasing its activity ...
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... explore the impact of BMI on AP severity, we conducted a literature review by searching the PubMed database from inception to January 2017). The terms "BMI" or "obese" and "acute pancreatitis" as well as "severe" or "severity" were used. A total of 118 studies were retrieved, as shown ( fig. S2). Seventy-nine studies were excluded, as they were not related to the subject of this review, as were 12 studies that were reviews/meta-analyses/hypotheses. The remaining studies were extensively reviewed for eligibility criteria, which were as follows: (i) clear BMI cutoff to define obesity, (ii) clear report of the incidence of mild ...
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... was divided into MAP and SAP and then into those that were obese versus nonobese. In cases where this was not explicitly clear, the communicating author was contacted (30,45), and the numbers so provided were included in the study. Papers that did not have adequate data or for reasons mentioned in the last column of fig. S1 and detailed in fig. S2 were excluded from the meta-analysis (n = 7). When more than one BMI cutoff was mentioned, the BMI used was the one at which the SAP risk ...

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... older, those with preexisting organ dysfunction), with hypertriglyceridemia, and/or pancreatic lipase-dependent lipotoxicity. (53)(54)(55) In many cases, signs and symptoms of MODS and MOF are present at initial assessment due to patient delay in seeking medical attention for their conditions and/or systems associated delays. In contrast, others present early in the course before these signs and symptoms develop resulting in underestimation of the severity of the evolving clinical course since MODS and MOF may take up to 24 hours or longer to develop. ...
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... The ACSL5 (Acyl-CoA synthetase long chain family member 5) found in this region prefers LCFA as a substrate for the formation of acyl-CoAs, which are then used to synthesize complex lipids or enter mitochondria for beta-oxidation [68]. Another candidate gene in this region is the pancreatic triglyceride lipase (PNLIP) gene, which encodes the lipolytic enzymes that mediate the digestion and absorption of dietary fat [69,70]. During pancreatitis in humans, PNLIP content increased in adipose tissue and entered visceral adipocytes, inhibiting mitochondrial complexes I and V through the production of long-chain NEFA by hydrolyzing adipose TAG [71]. ...
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... 22 Additionally, cooling can slow the lipolytic lipotoxic pathways in severe pancreatitis. 2,4,5,23,24 No single drug therapy has been effective in treating established acute pancreatitis. For example, targeting serine proteases with gabexate mesylate, 25 reactive oxygen species (ROS) with allopurinol, 26 and platelet-activating factor with lexipafant, 27 showed no benefit in clinical trials. ...
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... Although LC-UFAs are widely recognized for their anti-inflammatory effects, high concentrations of LC-UFAs induce the necrosis of PACs, which increases the release of cell contents via cell membrane rupture. This, in turn, contributes to an amplified inflammatory response and hastens the development of AP [5,8,9]. Furthermore, fatty acid metabolites, such as fatty acid chlorohydrin and fatty acid ethyl esters (FAEEs) are involved in damaging PACs [10,11]. ...
... Conversely, OA alleviated lipid toxicity [30,31]. However, the impact of OA on PACs, whether protective or detrimental, is concentration-dependent [8,9,32]. ...
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... This generates high lipotoxic-free fatty acid levels that worsen inflammation and organ failure. [100] The findings provide a potential explanation for the "obesity paradox" in AP, where obesity sometimes seems protective. The results suggest dietary fat saturation, not just the amount of body fat, contributes to pancreatitis severity through effects on lipotoxicity. ...
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... 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]. ...
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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.