Impurity contribution to ultraviolet absorption of saturated fatty acids
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ABSTRACT:
SUBMITTER: Saito S
PROVIDER: S-EPMC10511181 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Project description:Recent studies have identified a cholestatic variant of nonalcoholic fatty liver disease (NAFLD) with portal inflammation and ductular reaction. Based on reports of biliary damage, as well as increased circulating free fatty acids (FFAs) in NAFLD, we hypothesized the involvement of cholangiocyte lipoapoptosis as a mechanism of cellular injury. Here, we demonstrate that the saturated FFAs palmitate and stearate induced robust and rapid cell death in cholangiocytes. Palmitate and stearate induced cholangiocyte lipoapoptosis in a concentration-dependent manner in multiple cholangiocyte-derived cell lines. The mechanism of lipoapoptosis relied on the activation of caspase 3/7 activity. There was also a significant up-regulation of the proapoptotic BH3-containing protein, PUMA. In addition, palmitate-induced cholangiocyte lipoapoptosis involved a time-dependent increase in the nuclear localization of forkhead family of transcription factor 3 (FoxO3). We show evidence for posttranslational modification of FoxO3, including early (6 hours) deacetylation and dephosphorylation that coincide with localization of FoxO3 in the nuclear compartment. By 16 hours, nuclear FoxO3 is both phosphorylated and acetylated. Knockdown studies confirmed that FoxO3 and its downstream target, PUMA, were critical for palmitate- and stearate-induced cholangiocyte lipoapoptosis. Interestingly, cultured cholangiocyte-derived cells did not accumulate appreciable amounts of neutral lipid upon FFA treatment.Our data show that the saturated FFAs palmitate and stearate induced cholangiocyte lipoapoptosis by way of caspase activation, nuclear translocation of FoxO3, and increased proapoptotic PUMA expression. These results suggest that cholangiocyte injury may occur through lipoapoptosis in NAFLD and nonalcoholic steatohepatitis patients.
| S-EPMC4553418 | biostudies-literature
Project description:IntroductionObesity during pregnancy increases the risk for maternal complications like gestational diabetes, preeclampsia, and maternal inflammation. Maternal obesity also increases the risk of childhood obesity, intrauterine growth restriction (IUGR) and diabetes to the offspring. Increased circulating free fatty acids (FFAs) in obesity due to adipose tissue lipolysis induces lipoapoptosis to hepatocytes, cholangiocytes, and pancreatic-β-cells. During the third trimester of human pregnancy, there is an increase in maternal lipolysis and release of FFAs into the circulation. It is currently unknown if increased FFAs during gestation as a result of maternal obesity cause placental cell lipoapoptosis. Increased exposure of FFAs during maternal obesity has been shown to result in placental lipotoxicity. The objective of the present study is to determine saturated FFA-induced trophoblast lipoapoptosis and also to test the protective role of monounsaturated fatty acids against FFA-induced trophoblast lipoapoptosis using in vitro cell culture model. Here, we hypothesize that saturated FFAs induce placental trophoblast lipoapoptosis, which was prevented by monounsaturated fatty acids.MethodsBiochemical and structural markers of apoptosis by characteristic nuclear morphological changes with DAPI staining, and caspase 3/7 activity was assessed. Cleaved PARP and cleaved caspase 3 were examined by western blot analysis.ResultsTreatment of trophoblast cell lines, JEG-3 and JAR cells with palmitate (PA) or stearate (SA) induces trophoblast lipoapoptosis as evidenced by a significant increase in apoptotic nuclear morphological changes and caspase 3/7 activity. We observed that saturated FFAs caused a concentration-dependent increase in placental trophoblast lipoapoptosis. We also observed that monounsaturated fatty acids like palmitoleate and oleate mitigates placental trophoblast lipoapoptosis caused due to PA exposure.ConclusionWe show that saturated FFAs induce trophoblast lipoapoptosis. Co-treatment of monounsaturated fatty acids like palmitoleate and oleate protects against FFA-induced trophoblast lipoapoptosis.
| S-EPMC8062006 | biostudies-literature
Project description:Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity. However, the precise nature of other FFA and phospholipid changes in specific areas of the brain during learning is unknown. Here, using a targeted lipidomics approach to characterise FFAs and phospholipids across the rat brain, we demonstrated that the highest concentrations of these analytes were found in areas of the brain classically involved in fear learning and memory, such as the amygdala. Auditory fear conditioning led to an increase in saturated (particularly myristic and palmitic acids) and to a lesser extent unsaturated FFAs (predominantly arachidonic acid) in the amygdala and prefrontal cortex. Both fear conditioning and changes in FFA required activation of NMDA receptors. These results suggest a role for saturated FFAs in memory acquisition.
| S-EPMC8187648 | biostudies-literature
Project description:Toll-like receptor 4 (TLR4) and TLR2 were shown to be activated by saturated fatty acids (SFAs) but inhibited by docosahexaenoic acid (DHA). However, one report suggested that SFA-induced TLR activation in cell culture systems is due to contaminants in BSA used for solubilizing fatty acids. This report raised doubt about proinflammatory effects of SFAs. Our studies herein demonstrate that sodium palmitate (C16:0) or laurate (C12:0) without BSA solubilization induced phosphorylation of inhibitor of nuclear factor-?B ?, c-Jun N-terminal kinase (JNK), p44/42 mitogen-activated-kinase (ERK), and nuclear factor-?B subunit p65, and TLR target gene expression in THP1 monocytes or RAW264.7 macrophages, respectively, when cultured in low FBS (0.25%) medium. C12:0 induced NF?B activation through TLR2 dimerized with TLR1 or TLR6, and through TLR4. Because BSA was not used in these experiments, contaminants in BSA have no relevance. Unlike in suspension cells (THP-1), BSA-solubilized C16:0 instead of sodium C16:0 is required to induce TLR target gene expression in adherent cells (RAW264.7). C16:0-BSA transactivated TLR2 dimerized with TLR1 or TLR6 and through TLR4 as seen with C12:0. These results and additional studies with the LPS sequester polymixin B and in MyD88(-/-) macrophages indicated that SFA-induced activation of TLR2 or TLR4 is a fatty acid-specific effect, but not due to contaminants in BSA or fatty acid preparations.
| S-EPMC3413240 | biostudies-literature
Project description:ObjectiveThe role of saturated fatty acids (SFAs) in chronic disease remains controversial; inflammation is one pathway by which SFAs influence the risk for chronic disease. The aim of this study was to investigate the associations between red blood cell (RBC) phospholipid SFAs and systemic inflammation.MethodsAs part of a randomized controlled trial, we measured RBC phospholipid FA composition in 55 generally healthy adults twice at 3-mo intervals. We estimated associations of RBC total SFAs and two major SFA subtypes, palmitic and stearic acids, with C-reactive protein (CRP), interleukin (IL)-6, white blood count (WBC), and a composite inflammation measure using generalized estimating equations in multivariable FA substitution models.ResultsMean (±SD) SFA level across both visits was 45% ± 3% of the total RBC FAs, mainly palmitic (21% ± 1%) and stearic (17% ± 3%) acids. In models adjusted for age, sex, race, smoking, body mass index, statin use, aspirin use, transunsaturated FAs, and ω-3 FAs, SFAs were significantly associated with IL-6 (20% increase per 1 SD increment; 95% confidence interval [CI], 0.03%-43%; P = 0.05) and the composite inflammation measure (P = 0.05) and marginally associated with CRP (34% increase; 95% CI, -1% to 81%; P = 0.06), but not associated with WBC. Stearic acid was positively associated with CRP (35% increase; 95% CI, 2%-79%; P = 0.04). Palmitic acid was marginally associated with the composite inflammation measure (P = 0.06) and, upon additional ω-6 FA adjustment, significantly associated with IL-6 (15% increase; 95% CI, 0.4%-27%; P = 0.006).ConclusionsRBC SFAs, which represent longer-term dietary intake, are positively associated with inflammation. In particular, palmitic acid was associated with IL-6, and stearic acid was associated with CRP after multivariable adjustment.
| S-EPMC4185280 | biostudies-literature
Project description:Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans-unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well-established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids.
| S-EPMC5952403 | biostudies-literature
Project description:Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification.
| S-EPMC4665795 | biostudies-other
Project description:Study questionWhat are the effects of fatty acids on placental inflammatory cytokine with respect to toll-like receptor-4/nuclear factor-kappa B (TLR4/NF-kB)?Summary answerExogenous fatty acids induce a pro-inflammatory cytokine response in human placental cells in vitro via activation of TLR4 signaling pathways.What is known alreadyThe placenta is exposed to changes in circulating maternal fatty acid concentrations throughout pregnancy. Fatty acids are master regulators of innate immune pathways through recruitment of toll-like receptors and activation of cytokine synthesis.Study design, size, durationTrophoblast cells isolated from 14 normal term human placentas were incubated with long chain fatty acids (FA) of different carbon length and degree of saturation. The expression and secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Antibodies against TLR4 ligand binding domain, downstream signaling and anti-p65 NFkB-inhibitor were used to characterize the pathways of FA action.Participants/materials, setting, methodsGeneral approach used primary human term trophoblast cell culture. Methods and end-points used real-time quantitative PCR, cytokine measurements, immunohistochemistry, western blots.Main results and the role of chanceThe long chain saturated fatty acids, stearic and palmitic (PA), stimulated the synthesis as well as the release of TNF-α, IL-6 and IL-8 by trophoblast cells (2- to 6-fold, P < 0.001). In contrast, the unsaturated (palmitoleic, oleic, linoleic) acids did not modify cytokine expression significantly. Palmitate-induced inflammatory effects were mediated via TLR4 activation, NF-kB phosphorylation and nuclear translocation.Limitations, reasons for cautionTNF-α protein level was close to the limit of detection in the culture medium even when cells were cultured with PA.Wider implications of the findingsThese mechanisms open the way to a better understanding of how changes in maternal lipid homeostasis may regulate placental inflammatory status.Study funding/competing interestsX.Y. was recipient of fellowship award from West China Second University Hospital, Sichuan University (NIH HD 22965-19). The authors have nothing else to disclose.Trial registration numberNone.
| S-EPMC4635648 | biostudies-literature
Project description:RNA sequencing technology was applied to determine the transcriptional changes due to palmitate treatment, RNF213 knockdown, and GPAT4 knockdown.
2019-01-17 | GSE125178 | GEO
Project description:Epoxy nanofiltration membranes were fabricated by the step polymerization of a primary diamine and a diepoxide or triepoxide conomomer. Membrane selectivity and flux were tuned by changing the identity of the diepoxides and by increasing the concentration of triepoxides in the polymerization. The membranes were used to separate even chain length saturated fatty acids (FAs) and saturated fatty acid methyl esters (FAMEs) that possessed molecular weights between 80 - 300 g mol-1. Our membranes show excellent selectivities of up to 100:1 for the separation of the C4-C18 FAMEs. The flux of the FAMEs through the membranes showed an exponential dependence based on the number of carbons. Fabrication of thin epoxy membranes with thicknesses of 150 nm allowed for an increase in flux of FAMEs through the membrane and demonstrated that these separations can be used under industrially relevant conditions.
| S-EPMC5858744 | biostudies-literature