Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

Is There a FADS2-Modulated Link between Long-Chain Polyunsaturated Fatty Acids in Plasma Phospholipids and Polyphenol Intake in Adult Subjects Who Are Overweight?

Dietary polyphenols promote cardiometabolic health and are linked with long-chain polyunsaturated fatty acids in plasma phospholipids (LC-PUFA). The FADS2 polymorphisms are associated with LC-PUFA metabolism and overweight/obesity. This 4-week study examined the link between polyphenol intake, FADS2 variants (rs174593, rs174616, rs174576) and obesity in 62 overweight adults (BMI ≥ 25), allocated to consume 100 mL daily of either: Aronia juice, a rich source of polyphenols, with 1177.11 mg polyphenols (expressed as gallic acid equivalents)/100 mL (AJ, n = 22), Aronia juice with 294.28 mg polyphenols/100 mL (MJ, n = 20), or nutritionally matched polyphenol-lacking placebo as a control (PLB, n = 20). We analyzed LC-PUFA (% of total pool) by gas chromatography and FADS2 variants by real-time PCR. Four-week changes in LC-PUFA, BMI, and body weight were included in statistical models, controlling for gender and PUFA intake. Only upon AJ and MJ, the presence of FADS2 variant alleles affected changes in linoleic, arachidonic, and eicosapentaenoic acid (EPA). Upon MJ treatment, changes in EPA were inversely linked with changes in BMI (ß= -0.73, p = 0.029) and weight gain (ß= -2.17, p = 0.024). Only in subjects drinking AJ, the link between changes in EPA and anthropometric indices was modified by the rs174576 variant allele. Our results indicate the interaction between FADS2, fatty acid metabolism, and polyphenol intake in overweight subjects.

Walnut Consumption Induces Tissue-Specific Omega-6/Omega-3 Decrease in High-Fructose-Fed Wistar Rats.

Increased dietary, blood, and tissue n-6/n-3 fatty acid ratios are associated with obesity and metabolic syndrome. Due to Westernized dietary patterns, the increasing n-6/n-3 ratio is of growing concern worldwide, and dietary strategies aimed at its lowering are of public health importance. Walnuts are rich in dietary fats, and their consumption promotes cardiometabolic health. This study aimed to examine the effect of 6-week walnut consumption on tissue-specific n-6/n-3 ratio and fatty acid metabolic conversion in fructose-fed rats with a cluster of metabolic disorders. Male Wistar rats were fed a standard diet with or without 10% fructose in drinking water for 9 weeks. Diets of half of the animals were then supplemented with walnuts (2.4 g/day) for 6 weeks, upon which fatty acid profiles were determined in plasma, liver, adipose tissue, and kidney total lipids. Results showed that walnuts induced significant decreases in the n-6/n-3 content of total lipid pool in plasma and examined tissues, irrespective of metabolic burden. Walnut intervention decreased plasma and liver palmitoleic/palmitic, arachidonic/linoleic, and docosahexaenoic/α-linolenic acid ratios. It also modulated individual fatty acid levels by reducing arachidonic and palmitic acid and increasing α-linolenic, eicosapentaenoic, and docosapentaenoic acid in plasma and most tissues. Our study demonstrated that 6-week consumption of walnuts favorably modulated n-6/n-3 plasma and tissue ratio in male Wistar rats regardless of high-fructose feeding, underscoring the promising potential of walnuts in both prevention and treatment of the metabolic syndrome.

FADS2 polymorphisms are associated with plasma arachidonic acid and estimated desaturase-5 activity in a cross-sectional study.

Polymorphisms in FADS genes are associated with plasma long-chain polyunsaturated fatty acids (LC-PUFA) and modulate omega-6/omega-3 balance. We hypothesized that the FADS2 gene variants will be associated with lower product-to-precursor ratio in the fatty acid metabolic pathways. Thus, we explored FADS2 rs174593, rs174616, and rs174576 effects on plasma phospholipid fatty acid profile, markers of desaturase activities, and risk factors in a sample of apparently healthy Serbian adults. Food and nutrient intake data were compiled through 24 h recalls. Plasma phospholipid fatty acid content was assessed by gas-chromatography. Estimated desaturase activities were calculated as conversion rates towards LC-PUFA in omega-6 pathway. During the selection of FADS2 polymorphisms, we accounted for their positional and functional aspect. Genotyping was performed by Real-Time PCR. Multivariable-adjusted general linear and hierarchical regression models were applied. Study subjects (mean age = 40 ±â€¯7 years, 70% who were overweight) had a median dietary omega-6/omega-3 ratio of 16.29. Alternative allele frequencies were 33%, 36%, and 51% for rs174593, rs174576, and rs174616, respectively. Addition of FADS2 alternative alleles was associated with lower plasma arachidonic acid (AA, C20:4 n-6, P < .001) and estimated desaturase-5 activity (P < .001), irrespective of gender, age, daily polyunsaturated/saturated fatty acid intake, and obesity. The rs174576 association with AA withstood multiple testing and additional adjustments for other variants (multivariable-adjusted ß = -1.14 [95% CI: -2.25, -0.43]). None of the variants was associated with dietary intake, serum lipids, or obesity. We observed inverse associations between FADS2 variants and plasma AA but not omega-3 fatty acids in Serbian subjects, with rs174576 exhibiting the strongest relation.

Long-Chain Polyunsaturated Fatty Acids Are Associated with Blood Pressure and Hypertension over 10-Years in Black South African Adults Undergoing Nutritional Transition.

Nutritional transition in Africa is linked with increased blood pressure (BP). We examined 10-year fatty acid status and longitudinal associations between individual long-chain polyunsaturated fatty acids (PUFA), BP and status of hypertension (≥140/90 mmHg and/or medication use) in black South Africans. We included 300 adults (>30 years) participating in the Prospective Urban Rural Epidemiology study, and analysed data from three consecutive examinations (2005, 2010 and 2015 study years). Fatty acids in plasma phospholipids were analysed by gas chromatography-mass spectrometry. We applied sequential linear mixed models for continuous outcomes and generalized mixed models for the hypertension outcome, in the complete sample and separately in urban and rural subjects. Mean baseline systolic/diastolic BP was 137/89 mmHg. Ten-year hypertension status increased among rural (48.6% to 68.6%, p = 0.001) and tended to decrease among urban subjects (67.5% to 61.9%, p = 0.253). Regardless of urbanisation, n-6 PUFA increased and eicosapentaenoic acid (EPA, C20:5 n-3) decreased over the 10-years. Subjects in the highest tertile of arachidonic acid (C20:4 n-6) had 3.81 mmHg lower systolic (95% confidence interval (CI): -7.07, -0.54) and 3.82 mmHg lower diastolic BP (DBP) (95% CI: -5.70, -1.95) compared to the reference tertile, irrespective of lifestyle and clinical confounders. Similarly, osbond acid (C22:5 n-6) was inversely associated with DBP. Over the 10-years, subjects in the highest EPA tertile presented with +2.92 and +1.94 mmHg higher SBP and DBP, respectively, and with 1.46 higher odds of being hypertensive. In black South African adults, individual plasma n-6 PUFA were inversely associated with BP, whereas EPA was adversely associated with hypertension, supporting implementation of dietary fat quality in national cardiovascular primary prevention strategies.