Effects of NEFA unsaturation on their in vivo effects and unbound monomeric behavior. Serum MCP-1 (A), BUN (B), NEFA (C), uNEFA (D), and dsDNA (E) after intraperitoneally administering C16:0 (green), C18:1 (blue), and C18:2 (red) as mentioned below the x axis. Values are at necropsy if moribund or euthanasia at 72 hours. (F1) ITC thermograms of injecting NEFA or solvent (0.34% DMSO for C16:0 and PBS for C18:1 or C18:2) at concentrations mentioned below the NEFA into PBS (pH 7.4) at 37°C, and corresponding enthalpograms (F2) and CMCs (F3) shown as shaded rectangles in the areas where they intersect the x axis. Effect of exogenous albumin (final concentrations of 0.5%) on the cytosolic calcium (Cai) (G) and mitochondrial depolarization (m) (H and I) induced by 100 M of the indicated NEFA added at 100 s. (J and K) Comparison of the dose responses of increase in mitochondrial depolarization (m) after 60 s of addition of different concentration of C18:1 (blue) or C18:2 (red) in acini (J) and HEK293 cells (K). * indicates significant difference (P < 0.05) from the previous lower concentration by paired t test. # indicates a significant difference between C18:2 and C18:1 for that specific concentration on t test.

Effects of NEFA unsaturation on their in vivo effects and unbound monomeric behavior. Serum MCP-1 (A), BUN (B), NEFA (C), uNEFA (D), and dsDNA (E) after intraperitoneally administering C16:0 (green), C18:1 (blue), and C18:2 (red) as mentioned below the x axis. Values are at necropsy if moribund or euthanasia at 72 hours. (F1) ITC thermograms of injecting NEFA or solvent (0.34% DMSO for C16:0 and PBS for C18:1 or C18:2) at concentrations mentioned below the NEFA into PBS (pH 7.4) at 37°C, and corresponding enthalpograms (F2) and CMCs (F3) shown as shaded rectangles in the areas where they intersect the x axis. Effect of exogenous albumin (final concentrations of 0.5%) on the cytosolic calcium (Cai) (G) and mitochondrial depolarization (m) (H and I) induced by 100 M of the indicated NEFA added at 100 s. (J and K) Comparison of the dose responses of increase in mitochondrial depolarization (m) after 60 s of addition of different concentration of C18:1 (blue) or C18:2 (red) in acini (J) and HEK293 cells (K). * indicates significant difference (P < 0.05) from the previous lower concentration by paired t test. # indicates a significant difference between C18:2 and C18:1 for that specific concentration on t test.

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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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... LA concentrations in the fat pads of the UFAand SFA-fed ob/ob mice correspondingly matched reports of those in human adipose tissue from Japan [≈40% (25)] and the United States [5% (26)]. By 8 to 14 weeks, the mice 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 ...
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... induce inflammation and organ failure. LA [0.3% body weight (28, 53, 54)], OA (7), or PA (0.5%) body weight was instilled into the peritoneal cavity to simulate NEFA generated from visceral fat (2 to 10% body weight) lipolysis (64). Unlike LA and OA, there was no increase in circulating cytokines or organ failure (BUN increase) induced by PA (Fig. 6, A and B). The median survival for LA-treated mice was 18 hours and for OA was 64 hours, 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. ...
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... (64). Unlike LA and OA, there was no increase in circulating cytokines or organ failure (BUN increase) induced by PA (Fig. 6, A and B). The median survival for LA-treated mice was 18 hours and for OA was 64 hours, 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, ...
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... by PA (Fig. 6, A and B). The median survival for LA-treated mice was 18 hours and for OA was 64 hours, 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 ...
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... 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 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 ...
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... role of uNEFA in causing biological effects was then studied in cells. Addition of 100 M LA (below CMC) to pancreatic acini caused a larger increase in Cai (Fig. 6G) and m (Fig. 6H) than 100 M OA (above CMC). PA caused no change in these. A total of 0.5% albumin (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result ...
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... role of uNEFA in causing biological effects was then studied in cells. Addition of 100 M LA (below CMC) to pancreatic acini caused a larger increase in Cai (Fig. 6G) and m (Fig. 6H) than 100 M OA (above CMC). PA caused no change in these. A total of 0.5% albumin (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct ...
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... in causing biological effects was then studied in cells. Addition of 100 M LA (below CMC) to pancreatic acini caused a larger increase in Cai (Fig. 6G) and m (Fig. 6H) than 100 M OA (above CMC). PA caused no change in these. A total of 0.5% albumin (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct mechanisms of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai ...
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... (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct mechanisms of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai by albumin (Fig. 6G) and explains the cell death noted from LA or OA in previous studies (6). Therefore, the greater Cai and m induced by LA than OA at 100 M (Fig. 6, G and H) may be due to LA's higher CMC (Fig. 6F3) and thus explains the higher ...
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... This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct mechanisms of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai by albumin (Fig. 6G) and explains the cell death noted from LA or OA in previous studies (6). Therefore, the greater Cai and m induced by LA than OA at 100 M (Fig. 6, G and H) may be due to LA's higher CMC (Fig. 6F3) and thus explains the higher uNEFA levels and shorter survival noted in LA-treated mice. We tested this by measuring the dose response of ...
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... of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai by albumin (Fig. 6G) and explains the cell death noted from LA or OA in previous studies (6). Therefore, the greater Cai and m induced by LA than OA at 100 M (Fig. 6, G and H) may be due to LA's higher CMC (Fig. 6F3) and thus explains the higher uNEFA levels and shorter survival noted in LA-treated mice. We tested this by measuring the dose response of increase in m over baseline , and dsDNA (E) after intraperitoneally administering C16:0 (green), C18:1 (blue), and C18:2 (red) as mentioned below ...
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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 ...
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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 ...
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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 and OA (60 M), unlike PA, also reduced endothelial barrier integrity ( fig. S15, D and E), potentially explaining the ...
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... 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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... 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 ...
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... the argument in favor of the genetic or chronic effects of obesity such as insulin resistance and atherosclerosis in explaining these outcomes. The deleterious effects that we note with GTL are also seen with the triglyceride of OA but not with GTP during pancreatitis (5). These along with the deleterious effect of monomeric unsaturated NEFA (Fig. 6), lipase (16)(17)(18), and NEFA elevation (19,20,23), being associated with worse outcomes in other diseases states including COVID-19 (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 ...

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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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Background Innate immunity and metabolites link to the pathogenesis and severity of acute pancreatitis (AP). However, liver metabolism and its role in immune response and AP progression remain elusive. We investigated the function of liver metabolism in the pathogenesis of AP. Methods Circulating ketone body β-hydroxybutyrate (βOHB) levels were determined in AP clinical cohorts and caerulein-induced AP (CER-AP) mouse models receiving seven (Cer*7) or twelve (Cer*12) injection regimens at hourly intervals. Liver transcriptomics and metabolomics were compared between CER-AP (Cer*7) and CER-AP (Cer*12). Inhibition of fatty acid β-oxidation (FAO)-ketogenesis, or supplementation of βOHB was performed in mouse models of AP. The effect and mechanism of βOHB were examined in vitro. Findings Elevated circulating βOHB was observed in patients with non-severe AP (SAP) but not SAP. These findings were replicated in CER-AP (Cer*7) and CER-AP (Cer*12), which manifested as limited and hyperactive immune responses, respectively. FAO-ketogenesis was activated in CER-AP (Cer*7), while impaired long-chain FAO and mitochondrial function were observed in the liver of CER-AP (Cer*12). Blockage of FAO-ketogenesis (Cpt1a antagonism or Hmgcs2 knockdown) worsened, while supplementation of βOHB or its precursor 1,3-butanediol alleviated the severity of CER-AP. Mechanistically, βOHB had a discernible effect on pancreatic acinar cell damage, instead, it greatly attenuated the activation of pancreatic and systemic proinflammatory macrophages via class I histone deacetylases. Interpretation Our findings reveal that hepatic ketogenesis is activated as an endogenous protective programme to restrain AP progression, indicating its potential therapeutic value. Funding This work was supported by the National Natural Science Foundation of China, Shanghai Youth Talent Support Programme, and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant.
... 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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We compared 3 hospitalized patient cohorts and did mechanistic studies to determine if lipotoxicity worsens COVID-19. Cohort-1 (n=30) compared COVID-19 patients dismissed home to those requiring intensive-care unit (ICU) transfer. Cohort-2 (n=116) compared critically ill ICU patients with and without COVID-19. Cohort-3 (n=3969) studied hypoalbuminemia and hypocalcemia’s impact on COVID-19 mortality. Patients requiring ICU transfer had higher serum albumin unbound linoleic acid (LA). Unbound fatty acids and LA were elevated in ICU transfers, COVID-19 ICU patients and ICU non-survivors. COVID-19 ICU patients (cohort-2) had greater serum lipase, damage-associated molecular patterns (DAMPs), cytokines, hypocalcemia, hypoalbuminemia, organ failure and thrombotic events. Hypocalcemia and hypoalbuminemia independently associated with COVID-19 mortality in cohort-3. Experimentally, LA reacted with albumin, calcium and induced hypocalcemia, hypoalbuminemia in mice. Endothelial cells took up unbound LA, which depolarized their mitochondria. In mice, unbound LA increased DAMPs, cytokines, causing endothelial injury, organ failure and thrombosis. Therefore, excessive unbound LA in the circulation may worsen COVID-19 outcomes.
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