Differences in Plasma Fatty Acid Composition Related to Chronic Pancreatitis: A Pilot Study.

OBJECTIVES: Chronic pancreatitis (CP) is an inflammatory disease affecting the absorption of fat-soluble nutrients. Signaling in pancreatic cells that lead to inflammation may be influenced by fatty acids (FAs) through diet and de novo lipogenesis. Here, we investigated the relationship between plasma FA composition in CP with heterogeneity of etiology and complications of CP. MATERIALS AND METHODS: Blood and clinical parameters were collected from subjects with CP (n = 47) and controls (n = 22). Plasma was analyzed for FA composition using gas chromatography and compared between controls and CP and within CP. RESULTS: Palmitic acid increased, and linoleic acid decreased in CP compared with controls. Correlations between age or body mass index and FAs are altered in CP compared with controls. Diabetes, pancreatic calcifications, and substance usage, but not exocrine pancreatic dysfunction, were associated with differences in oleic acid and linoleic acid relative abundance in CP. De novo lipogenesis index was increased in the plasma of subjects with CP compared with controls and in calcific CP compared with noncalcific CP. CONCLUSIONS: Fatty acids that are markers of de novo lipogenesis and linoleic acid are dysregulated in CP depending on the etiology or complication. These results enhance our understanding of CP and highlight potential pathways targeting FAs for treating CP.

Autophagy Induced by Palmitic Acid Regulates Neutrophil Adhesion Through the Granule-Dependent Degradation of αMß2 Integrin in Dairy Cows With Fatty Liver.

ß2 integrins are critical for neutrophil firm adhesion, trans-endothelial migration, and the recruitment to the inflamed tissue. Autophagy is implicated in cell migration and tumor metastasis through facilitating the turnover of ß1 integrins; however, whether autophagy is able to control neutrophil migration by promoting the degradation of ß2 integrins is unexplored. Here, we show that high blood levels of palmitic acid (PA) strongly triggered neutrophil autophagy activation, leading to adhesion deficiency in dairy cows with fatty liver. The three neutrophil granule subtypes, namely, azurophil granules (AGs), specific granules (SGs), and gelatinase granules (GGs), were engulfed by the autophagosomes for degradation, resulting in an increased vacuolation in fatty liver dairy cow neutrophils. Importantly, the adhesion-associated molecules CD11b and CD18 distributed on AGs, SGs, and GGs were degraded with the three granule subtypes by autophagy. Moreover, FGA, Hsc70, and TRIM21 mediated the degradation of cytosolic oxidized-ubiquitinated CD11b and CD18. Collectively, our results demonstrate that high blood PA triggers neutrophil autophagy-dependent vacuolation and granule-dependent adhesion deficiency, decreasing neutrophil mobility, and impairing the innate immune system of dairy cow with fatty liver. This theory extends the category of autophagy in maintaining granule homeostasis and provides a novel strategy to improve the immune of dairy cows with metabolic disease.

Group 3 Innate Lymphoid Cells Protect Steatohepatitis From High-Fat Diet Induced Toxicity.

Background and Aims: Emerging evidence has revealed that innate lymphoid cells (ILCs) play a key role in regulating metabolic disorders. Here, we investigated the role of group 3 ILCs (ILC3s) in the modulation of Non-alcoholic fatty liver disease (NAFLD). Methods: RORγ gfp/gfp (RORgt KI/KI) and Rag2-/- mice with the administration of A213, RORgt antagonist, fed with a high-fat-diet (HFD) for 12 weeks, were used. We performed flow cytometry, real time PCR, and lipidomics analysis of serum and liver, and used RAW264.7 cells and murine primary hepatocytes in vitro. Results: HFD increased ILC3s and M1 macrophages in the liver, and RORgt KI/KI mice deficient in ILC3 showed significant fatty liver, liver fibrosis and significantly increased palmitic acid levels in serum and liver. In addition, administration of A213 to Rag2-/- mice caused significant fatty liver, liver fibrosis, and a significant increase in serum and liver palmitate concentrations, as in RORgt KI/KI mice. Addition of palmitc acid stimulated IL-23 production in cell experiments using RAW264.7. IL-22 produced by ILC3s inhibited the palmitate-induced apoptosis of primary hepatocytes. Conclusions: HFD stimulates IL-23 production by M1 macrophages, thus promoting ILC3 proliferation, whereas IL-22 secreted by ILC3s contributes to the upregulation of hepatic lipid metabolism and has anti-apoptosis activity.

Silibinin improves nonalcoholic fatty liver by regulating the expression of miR­122: An in vitro and in vivo study.

Silibinin is a flavonoid that improves fatty liver and insulin resistance. To elucidate the effect of silibinin on lipid deposition and the potential molecular mechanism, the present study conducted in vivo and in vitro experiments. In the in vivo experiments, mice were randomly divided into control, high­fat and silibinin groups, while HepG2 cells were randomly divided into control, palmitic acid intervention and silibinin intervention groups. The mRNA, protein and miR­122 expression associated with hepatic lipid metabolism were detected in each group. The results demonstrated that silibinin reduced the triglyceride content, miR­122 expression and the mRNA and protein expressions of fatty acid synthase (FAS) and acetyl­CoA carboxylase (ACC). Silibinin increased the mRNA and protein expression of carnitine palmitoyl transferase 1A (CPT1A). In the present study, HepG2 cells cultured with palmitate were treated with silibinin following overexpression of micro RNA (miR) 122. The results demonstrated that the mRNA and protein expression of FAS and ACC was increased, while that of CPT1A was decreased. Therefore, it could be deduced that silibinin improved lipid metabolism by reducing the expression of miR­122 and inhibiting the expression of miR­122 may be a new therapeutic target to improve fatty liver disease.

Endotypes of primary osteoarthritis identified by plasma metabolomics analysis.

OBJECTIVE: To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. METHODS: Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. RESULTS: Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009). CONCLUSION: Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

Palmitic acid induces inflammation in placental trophoblasts and impairs their migration toward smooth muscle cells through plasminogen activator inhibitor-1.

A critical component of early human placental development includes migration of extravillous trophoblasts (EVTs) into the decidua. EVTs migrate toward and displace vascular smooth muscle cells (SMCs) surrounding several uterine structures, including spiral arteries. Shallow trophoblast invasion features in several pregnancy complications including preeclampsia. Maternal obesity is a risk factor for placental dysfunction, suggesting that factors within an obese environment may impair early placental development. Herein, we tested the hypothesis that palmitic acid, a saturated fatty acid circulating at high levels in obese women, induces an inflammatory response in EVTs that hinders their capacity to migrate toward SMCs. We found that SMCs and SMC-conditioned media stimulated migration and invasion of an EVT-like cell line, HTR8/SVneo. Palmitic acid impaired EVT migration and invasion toward SMCs, and induced expression of several vasoactive and inflammatory mediators in EVTs, including endothelin, interleukin (IL)-6, IL-8 and PAI1. PAI1 was increased in plasma of women with early-onset preeclampsia, and PAI1-deficient EVTs were protected from the anti-migratory effects of palmitic acid. Using first trimester placental explants, palmitic acid exposure decreased EVT invasion through Matrigel. Our findings reveal that palmitic acid induces an inflammatory response in EVTs and attenuates their migration through a mechanism involving PAI1. High levels of palmitic acid in pathophysiological situations like obesity may impair early placental development and predispose to placental dysfunction.

Impact of the used solvent on the reconstitution efficiency of evaporated biosamples for untargeted metabolomics studies.

INTRODUCTION: Untargeted metabolomics intends to objectively analyze a wide variety of compounds. Their diverse physicochemical properties make it difficult to choose an appropriate reconstitution solvent after sample evaporation without influencing the chromatography or hamper column sorbent integrity. OBJECTIVES: The study aimed to identify the most appropriate reconstitution solvent for blood plasma samples in terms of feature recovery, four endogenous compounds, and one selected internal standard. METHODS: We investigated several reconstitution solvent mixtures containing acetonitrile and methanol to resolve human plasma extract and evaluated them concerning the peak areas of tryptophan-d5, glucose, creatinine, palmitic acid, and the phophatidylcholine PC(P-16:0/P-16:0), as well as the total feature count RESULTS: Results indicated that acetonitrile containing 30% methanol was best suited to match all tested criteria at least for human blood plasma samples. CONCLUSION: Despite identifying the mixture of acetonitrile and methanol being suitable as solvent for human blood plasma extracts, we recommend to systematically test for an appropriate reconstitution solvent for each analyzed biomatrix.

Features of serum fatty acids in acute ischaemic stroke patients aged 50 years or older.

BACKGROUND: Serum fatty acid (s-FA) compositions and their correlation with serum lipids (s-LPs) such as total cholesterol (T-CHO) and triglycerides (TG) have been reported in healthy young subjects. However, little is known about such features in acute ischaemic stroke (AIS). The aim of our study was to investigate s-FA characteristics and their correlation with AIS in elderly patients. METHODS: We conducted a cross-sectional study of patients aged 50 years or older who were admitted between September 2015 and March 2017 within 24 h of the first AIS onset. We evaluated concentrations and compositions of s-FAs and their association with s-LPs, age, and ischaemic stroke subtypes, including large-artery atherosclerosis (LAA), small-vessel occlusion (SVO), and cardioembolism (CE) or others. RESULTS: One hundred ninety-one patients met our inclusion criteria. Their average age was 74.4 years, mean T-CHO and median TG were 203.4 and 94.5 mg/dl, respectively, and median or mean concentrations of palmitic acid (PA), oleic acid (OlA), linoleic acid (LiA), and docosahexaenoic acid (DHA) were 680.7, 602.5, 795.2, and 136.9 µg/ml, respectively, with mean compositions of 23.7, 21.3, 27.1, and 4.4%, respectively. PA, OlA, and LiA concentrations were weakly negatively associated with age and positively correlated with TG. In LAA or SVO (LAA_SVO) and CE or others (CE_O), mean age was 71.9 and 77.4 years (p < 0.001), mean T-CHO was 213.9 and 191.2 mg/dl (p < 0.0001), median TG was 106.5 and 88.5 mg/dl (p < 0.01), median PA was 717.2 and 648.4 µg/ml (p < 0.01), median OlA was 638.2 and 567.5 µg/ml (p < 0.01), and median LiA was 844.7 and 728.5 µg/ml (p < 0.01), respectively. DHA composition was weakly positively correlated with age. There were no differences in PA, OlA, LiA, and DHA compositions between LAA_SVO and CE_O. CONCLUSIONS: In AIS elderly patients, concentrations, rather than compositions of PA, OlA, and LiA, correlated with age, TG, and ischaemic stroke subtypes. Patients with LAA_SVO were younger and had higher concentrations of PA, OlA, and LiA than those with CE_O. There were no differences in such compositions between LAA_SVO and CE_O.

Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

Evaluation of the Stability of Fatty Acids in Erythrocytes from Human Umbilical Cord.

The interest in the amount of polyunsaturated fatty acids (PUFA) in the umbilical cord blood (UCB) is increasing, but the stability of erythrocyte PUFA in these samples during storage and washing of the erythrocytes has not been directly evaluated. The purpose of this study was to analyze the effect of the lapse of time on the fatty acid (FA) content from UCB sample collection and maintained at 4 °C (0-12 h) until erythrocyte separation and washing. Palmitic acid (16:0), stearic acid (18:0), 18:1n-7/n-9, linoleic acid (18:2n-6), arachidonic acid (20:4n-6), 22:4n-6, eicosapentaenoic acid (20:5n-3), docosapentaenoic acid (22:5n-3), and docosahexaenoic acid (22:6n-3) together accounted for 87% of the FA profile in the umbilical vein erythrocytes. No difference was observed in the concentration of any of the FA studied, nor in the sum of saturated fatty acids (SFA), PUFA, or LC-PUFA in umbilical erythrocytes obtained at delivery and stored up to 12 h before the separation of erythrocytes. However, if a washing step was included in the processing of the erythrocytes, a decrease in the concentration of 16:0, 18:0, 18:3n-3, 20:4n-6, 22:4n-6, total SFA, PUFA, LC-PUFA, and n-6 LC-PUFA was evidenced, compared to unwashed erythrocytes. The FA concentration in umbilical cord erythrocytes did not change between samples stored from 0 to 12 h until erythrocyte separation. Erythrocyte washing before storage decreased the concentration of significant individual and total SFA, PUFA, and LC-PUFA. These results should be considered when planning the collection of UCB samples for the study of fatty acid concentration due to the nonscheduled timing of deliveries.

Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study.

Background Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6 years, and 13 years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13 years, median follow-up (maximum 22.4 years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95% CI=1.08-1.41; and hazard ratio=0.78, 95% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.

Circulating Saturated Fatty Acids and Incident Type 2 Diabetes: A Systematic Review and Meta-Analysis.

The effect of saturated fatty acids (SFAs) on incident type 2 diabetes (T2D) is controversial and few have systematically appraised the evidence. We conducted a comprehensive search of prospective studies examining these relationships that were published in PubMed, Web of Science, or EMBASE from 21 February 1989 to 21 February 2019. A total of 19 studies were included for systematic review and 10 for meta-analysis. We estimated the summarized relative risk (RR) and 95% confidence interval (95% CI) using a random (if I2 > 50%) or a fixed effects model (if I2 ≤ 50%). Although the included studies reported inconclusive results, the majority supported a protective effect of odd-chain and an adverse impact of even-chain SFAs. Meta-analysis showed that the per standard deviation (SD) increase in odd-chain SFAs was associated with a reduced risk of incident T2D (C15:0: 0.86, 0.76-0.98; C17:0: 0.76, 0.59-0.97), while a per SD increase in one even-chain SFA was associated with an increased risk of incident T2D (C14:0: 1.13, 1.09-1.18). No associations were found between other SFAs and incident T2D. In conclusion, our findings suggest an overall protective effect of odd-chain SFAs and the inconclusive impact of even- and very-long-chain SFAs on incident T2D.

Palm Oil and Beta-palmitate in Infant Formula: A Position Paper by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee on Nutrition.

BACKGROUND: Palm oil (PO) is used in infant formulas in order to achieve palmitic acid (PA) levels similar to those in human milk. PA in PO is esterified predominantly at the SN-1,3 position of triacylglycerol (TAG), and infant formulas are now available in which a greater proportion of PA is in the SN-2 position (typical configuration in human milk). As there are some concerns about the use of PO, we aimed to review literature on health effects of PO and SN-2-palmitate in infant formulas. METHODS: PubMed and Cochrane Database of Systematic Reviews were systematically searched for relevant studies on possible beneficial effects or harms of either PO or SN-2-palmitate in infant formula on various health outcomes. RESULTS: We identified 12 relevant studies using PO and 21 studies using SN-2-palmitate. Published studies have variable methodology, subject characteristics, and some are underpowered for the key outcomes. PO is associated with harder stools and SN-2-palmitate use may lead to softer stool consistency. Bone effects seem to be short-lasting. For some outcomes (infant colic, faecal microbiota, lipid metabolism), the number of studies is very limited and summary evidence inconclusive. Growth of infants is not influenced. There are no studies published on the effect on markers of later diseases. CONCLUSIONS: There is insufficient evidence to suggest that PO should be avoided as a source of fat in infant formulas for health reasons. Inclusion of high SN-2-palmitate fat blend in infant formulas may have short-term effects on stool consistency but cannot be considered essential.

Advanced Liver Fibrosis Is Independently Associated with Palmitic Acid and Insulin Levels in Patients with Non-Alcoholic Fatty Liver Disease.

Changes in lipid metabolism occur during the development and progression non-alcoholic fatty liver disease (NAFLD). However, the fatty acid (FA) profile in red blood cells (RBC) from patients with liver fibrosis remains unexplored. Thus, the goal of this study was to evaluate the fatty acid profile in RBC, dietary lipid intake and insulin resistance indicators in patients with NAFLD, according to the degree of hepatic fibrosis. Using elastography, patients were classified with (n = 52) and without (n = 37) advanced liver fibrosis. The fatty acid profile in RBC was analyzed using gas chromatography and the lipid intake was evaluated through a 24-h dietary recall. Subjects with advanced liver fibrosis had higher levels of palmitic, stearic and oleic acid and total monounsaturated fatty acid (MUFA) and insulin (p < 0.05), and lower levels of elongase very long chain fatty acids protein-6 and the delta-5-desaturase enzymatic activity (p < 0.05). These results suggest a lack of regulation of enzymes related to FA metabolism in patients with advanced fibrosis.

Erythrocyte Saturated Fatty Acids and Incident Type 2 Diabetes in Chinese Men and Women: A Prospective Cohort Study.

The association between circulating saturated fatty acids (SFAs) and incident type 2 diabetes (T2D) is reported in Western populations with inconsistent results, while evidence from Asian populations is scarce. We aimed to examine the associations between erythrocyte SFAs and incident T2D in a Chinese population. Between 2008 and 2013, a total of 2683 participants, aged 40⁻75 years, free of diabetes were included in the present analyses. Incident T2D cases were ascertained during follow-up visits. Gas chromatography was used to measure erythrocyte fatty acids at baseline. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). During 13,508 person years of follow-up, 216 T2D cases were identified. Compared with the first quartile, multivariable-adjusted HRs (95% CIs) of the fourth quartile were 1.20 (0.82⁻1.76; p = 0.242) for myristic acid (14-carbon tail, zero double bonds; 14:0), 0.69 (0.48⁻0.99; p = 0.080) for palmitic acid (16:0), 1.49 (1.02⁻2.19; p = 0.047) for stearic acid (18:0), 1.46 (1.00⁻2.12; p = 0.035) for arachidic acid (20:0), 1.48 (0.99⁻2.22; p = 0.061) for behenic acid (22:0), and 1.08 (0.74⁻1.56; p = 0.913) for lignoceric acid (24:0). Our findings indicate that individual erythrocyte SFAs are associated with T2D in different directions, with 18:0 and 20:0 SFAs positively associated with the risk, whereas no convincing inverse association for 16:0 SFAs.

Natural Abundance Carbon Isotopic Analysis Indicates the Equal Contribution of Local Synthesis and Plasma Uptake to Palmitate Levels in the Mouse Brain.

Saturated fatty acids are the most abundant fatty acids in the brain, however, there has been some debate regarding the ability of intact dietary saturated fatty acids to be incorporated into the brain. In the present study, we use compound specific isotope analysis to measure the natural abundance carbon isotopic signature of brain, liver, and blood palmitic acid (PAM) and compare it to the dietary PAM and sugar isotopic signatures to calculate the relative contribution of both the incorporation of intact and endogenously synthesized PAM to these pools. Mice were equilibrated to the study diet, and extracted fatty acids were analyzed with gas chromatography isotope ratio mass spectrometry to determine the carbon isotopic signature of PAM (δ13 CPAM ). Liver, serum total, and serum unesterified fatty acid δ13 CPAM ranged between -20.6 and -21.1 mUr and were approximately 8.5 mUr more enriched in 13 C when compared to the dietary PAM signature. Brain δ13 CPAM was found to be more enriched than liver or blood pools (-16.7 ± 0.2 mUr, mean ± SD). Two end-member-mixed modeling using the carbon isotopic signature of dietary PAM and dietary sugars determined the contribution of synthesis to the total tissue PAM pool to range between 44% and 48%. This suggests that endogenous synthesis and dietary PAM are near equal contributors to brain, liver, and blood PAM pools. In conclusion, our data provide evidence that brain PAM levels are maintained by both local endogenous synthesis and through the uptake of intact PAM from the blood.

Free Fatty Acids: Circulating Contributors of Metabolic Syndrome.

Metabolic syndrome induces an increased cardiovascular morbidity and mortality. Most importantly, the prevalence of metabolic syndrome in adult population is expanding. Both clinical and preclinical studies indicate that increased Free Fatty Acids (FFAs) are involved in the pathogenesis of insulin resistance and subsequent development of metabolic syndrome. The relevance of FFAs in protecting and restoring tissue function is quite vast. The search to correlate the functional deterioration of the tissues within the cardiovascular system and increased plasma concentrations of FFAs has been reported. The importance of reduction in the consumption of dietary fatty acids along with the identification of dysregulated genes responsible for persistent increased FFAs uptake and mitochondrial ß-oxidation has been increasingly recognized. This review discusses the current empirical understanding of the different types of fatty acids and their metabolism and functions both in physiological and pathophysiological conditions. We also discuss in detail about the molecular and pathophysiological basis of increased FFAs, which augments Cardiovascular Disease (CVD).

Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. METHODS: Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study. The changes in serum metabolite levels were investigated using a gas chromatography-mass spectrometry-based metabolomics approach and underwent statistical analysis. RESULTS: Significant metabolic changes were observed on day 7. The stearic acid/palmitic acid (SA/PA) ratio was effective in the diagnosis of grade II-IV aGVHD. Multivariate analysis showed that patients with high SA/PA ratios on day 7 after HSCT were less likely to develop II-IV aGVHD than patients with low SA/PA ratios (odds ratio [OR] = 0.06, 95% CI 0.02-0.18, P < 0.001). After the adjustment for clinical characteristics, the SA/PA ratio had no significant effect on overall survival (hazard ratio [HR] = 1.95, 95% CI 0.92-4.14, P = 0.08), and patients in the high SA/PA ratio group were significantly more likely to relapse than those in the low ratio group (HR = 2.26, 95% CI 1.04-4.91, P = 0.04). CONCLUSION: Our findings suggest that the SA/PA ratio on day 7 after HSCT is an excellent biomarker to predict both aGVHD and relapse. The serum SA/PA ratio measured on day 7 after transplantation may improve risk stratification for aGVHD and relapse after allogeneic stem cell transplantation. FUNDING: National Natural Science Foundation of China (81470346, 81773361), Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Natural Science Foundation (BK20161204), Innovation Capability Development Project of Jiangsu Province (BM2015004), Jiangsu Medical Junior Talent Person award (QNRC2016707), and NIH (AI129582 and NS106170).

Ground Beef High in Total Fat and Saturated Fatty Acids Decreases X Receptor Signaling Targets in Peripheral Blood Mononuclear Cells of Men and Women.

We hypothesized that consumption of saturated fatty acids in the form of high-fat ground beef for 5 weeks would depress liver X receptor signaling targets in peripheral blood mononuclear cells (PBMC) and that changes in gene expression would be associated with the corresponding changes in lipoprotein cholesterol (C) concentrations. Older men (n = 5, age 68.0 ± 4.6 years) and postmenopausal women (n = 7, age 60.9 ± 3.1 years) were assigned randomly to consume ground-beef containing 18% total fat (18F) or 25% total fat (25F), five patties per week for 5 weeks with an intervening 4-week washout period. The 25F and 18F ground-beef increased (p < 0.05) the intake of saturated fat, monounsaturated fat, palmitic acid, and stearic acid, but the 25F ground-beef increased only the intake of oleic acid (p < 0.05). The ground-beefs 18F and 25F increased the plasma concentration of palmitic acid (p < 0.05) and decreased the plasma concentrations of arachidonic, eicosapentaenoic, and docosahexaenic acids (p < 0.05). The interventions of 18F and 25F ground-beef decreased very low-density lipoprotein C concentrations and increased particle diameters and low-density lipoprotein (LDL)-I-C and LDL-II-C concentrations (p < 0.05). The ground-beef 25F decreased PBMC mRNA levels for the adenosine triphosphate (ATP) binding cassette A, ATP binding cassette G1, sterol regulatory element binding protein-1, and LDL receptor (LDLR) (p < 0.05). The ground-beef 18F increased mRNA levels for stearoyl-CoA desaturase-1 (p < 0.05). We conclude that the increased LDL particle size and LDL-I-C and LDL-II-C concentrations following the 25F ground-beef intervention may have been caused by decreased hepatic LDLR gene expression.

Ceramide stearic to palmitic acid ratio predicts incident diabetes.

AIMS/HYPOTHESIS: Ceramide lipids have a role in the development of insulin resistance, diabetes and risk of cardiovascular disease. Here we investigated four ceramides and their ratios to find the best predictors of incident diabetes. METHODS: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. RESULTS: Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss. CONCLUSIONS/INTERPRETATION: The Cer(d18:1/18:0)/Cer(d18:1/16:0) ratio is an independent predictive biomarker for incident diabetes, and may be modulated by lifestyle intervention.