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Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism. This study recruited 138 monozygotic (MZ) and dizygotic (DZ) twins aged 18-65 years and measured serum oxylipins, endocannabinoids, bile acids and steroids using liquid chromatography mass-spectrometry (LC-MS). In this classic twin design, the similarities and differences between MZ and DZ twins are modelled to estimate the contribution of genetic and environmental influences to variation in lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxyeicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxyeicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)] and 14-hydroxydocosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with the endocannabinoid docosahexaenoylethanolamide [0.52 (95% CI: 0.15,0.72)]. For others such as 13-hydroxyoctadecatrienoic acid and lithocholic acid the contribution of environment to variation was stronger. With increased understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends pre-existing knowledge of the genetic and environmental influences on the human lipidome.

There was no relationship between these lipid markers and adiposity in this population; however, there were correlations with HOMA-IR. Regardless of adiposity, there may be underlying changes in fatty acid and lipid metabolism associated with the development of metabolic diseases.

BackgroundThe Dietary Guidelines for Americans (DGA) recommends consuming ~225 g/wk of a variety of seafood providing >1.75 g/wk of long-chain omega-3 fatty acids to reduce cardiovascular disease risk, however individual responses to treatment vary.ObjectiveThis study had three main objectives. First, to determine if a DGA-conforming diet (DGAD), in comparison to a typical American diet (TAD), can increase the omega-3 index (OM3I), i.e., the red blood cell mol% of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA). Second, to identify factors explaining variability in the OM3I response to dietary treatment. Third to identify factors associated with the baseline OM3I.DesignThis is a secondary analysis of a randomized, double-blind 8 wk dietary intervention of overweight/obese women fed an 8d rotating TAD (n = 20) or DGAD (n = 22) registered at www.clinicaltrials.gov as NCT02298725. The DGAD-group consumed 240 g/wk of Atlantic farmed salmon and albacore tuna in three meals with an estimated EPA + DHA of 3.7 ± 0.6 g/wk. The TAD-group consumed ~160 g/wk of farmed white shrimp and a seafood salad containing imitation crab in three meal with an estimated EPA + DHA of 0.45 ± 0.05 g/wk. Habitual diet was determined at baseline, and body composition was determined at 0 and 8wks. Red blood cell fatty acids were measured at 0, 2 and 8 wk.ResultsAt 8 wk, the TAD-group OM3I was unchanged (5.90 ± 1.35–5.80 ± 0.76%), while the DGAD-group OM3I increased (5.63 ± 1.27–7.33 ± 1.36%; p < 0.001). In the DGAD-group 9 of 22 participants achieved an OM3I >8%. Together, body composition and the baseline OM3I explained 83% of the response to treatment variability. Baseline OM3I (5.8 ± 1.3%; n = 42) was negatively correlated to the android fat mass (p = 0.0007) and positively correlated to the FFQ estimated habitual (EPA+DHA) when expressed as a ratio to total dietary fat (p = 0.006).ConclusionsAn 8 wk TAD did not change the OM3I of ~6%, while a DGAD with 240 g/wk of salmon and albacore tuna increased the OM3I. Body fat distribution and basal omega-3 status are primary factors influencing the OM3I response to dietary intake in overweight/obese women.

Background: The Dietary Guidelines for Americans (DGA) recommends consuming >1.75g/wk of long-chain omega-3 fatty acids to reduce the risk of cardiovascular disease (CVD) through triglyceride reduction, however individual responses to treatment vary. Objective: We sought to determine if a DGA-conforming diet (DGAD) can increase the omega-3 index (OM3I), a diet-sensitive biomarker of omega-3 fatty acid status, into a health promoting range and reduce fasting triglycerides in 8 weeks. We further explored determinants of the basal OM3I and its response to treatment. Design: This is a secondary analysis of a randomized, double-blind 8wk dietary intervention of overweight/obese women fed an 8d rotating DGAD (n =22) or typical American diet (TAD; n =20) registered at www.clinicaltrials.gov as NCT02298725. The DGAD and TAD provided individuals with 16 ± 2 g/wk and 1.2 ± 0.12 g/wk of eisocapentaenoic acid (EPA) + docosahexaenoic acid (DHA), respectively. Habitual diet and body composition were determined at baseline. OM3I, fasting triglycerides, glucose and insulin were measured at 0, 2 and 8wk. Results: Baseline OM3I (5.8 ± 1.3; n =42) was positively correlated to the dietary (EPA+DHA):dietary fat ratio (p =0.006), negatively correlated to the android fat mass (p =0.0007) and was not different between diet groups. At 8wk, while the TAD-group average OM3I was unchanged (5.8 ± 0.76), the DGAD-group OM3I increased (7.33 ± 1.36; p <0.001). In the DGAD-group 9 of 22 (i.e. 41%) participants achieving an OM3I >8%. Subgroup analyses of the DGAD-group revealed that body fat content and distribution influenced the baseline-dependent response to treatment. Fasting triglyceride and OM3I changes did not correlate. Conclusions: An 8wk TAD stabilized the OM3I in a healthy range, while a DGAD increased the OM3I into a health-promoting range, but did not reduce fasting triglycerides. Fat distribution and basal omega-3 status are primary factors influencing omega-3 efficacy in overweight/obese women.

Obligate intracellular bacteria shed essential biosynthetic pathways during their evolution towards host dependency, providing an opportunity for host-directed therapeutics. UsingRickettsiaceaeas a model, we employed a novel computational pipeline called PoMeLo to systematically compare this cytosolic family of bacteria to the relatedAnaplasmataceae, which reside in a membrane-bound vacuole in the host cell. We identified 20 metabolic pathways that have been lost since the divergence ofAnaplasmataceaeandRickettsiaceae, corresponding to the latter’s change to a cytosolic niche. We hypothesized that drug inhibition of these host metabolic pathways would reduce the levels of metabolites available to the bacteria, thereby inhibiting bacterial growth. We tested 22 commercially available inhibitors for 14 of the identified pathways and found that the majority (59%) reduced bacterial growth at concentrations that did not induce host cell cytotoxicity. Of these, 5 inhibitors with an IC50under 5 μM were tested to determine whether their mode of inhibition was bactericidal or bacteriostatic. Both mycophenolate mofetil, an inhibitor of inosine-5’-monophosphate dehydrogenase in the purine biosynthesis pathway, and roseoflavin, an analog of riboflavin, displayed bactericidal activity. A complementary unbiased mass spectrometry-based metabolomics approach identified 14 pathways impacted byRickettsiainfection based on alterations in metabolite levels. Strikingly, 11 of these (79%) overlapped with those identified by our computational predictions. Thesein vitrovalidation studies support the feasibility of a novel evolutionary genomics-guided approach for host-directed antibiotic drug development against obligate pathogens.ImportanceMany pathogens have evolved to acquire essential metabolites from their host cell, while in turn shedding their own biosynthetic capacities. This leads to an interesting dilemma: on one hand, reduced genomes allow pathogens to save energy and replicate more quickly, while on the other hand, they become more dependent on the host cell for survival. This vulnerability can be exploited by identifying and therapeutically inhibiting the host pathways that are essential for pathogen survival. The significance of our research is in predicting the precise pathways lost during a pathogen’s evolutionary adaptation to parasitism and validating these predictions through targetedin vitrogrowth assays and an unbiased metabolomic survey of the host-pathogen interface.

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