Histone H3K4me3 modification is a transgenerational epigenetic signal for lipid metabolism in Caenorhabditis elegans

As a major risk factor to human health, obesity presents a massive burden to people and society. Interestingly, the obese status of parents could affect progeny’s lipid accumulation through multi-generational epigenetic inheritance. To date, many questions remain as to how lipid accumulation leads to signals that are transmitted across generations. In this study, we established a model of C. elegans fed with a high fat diet (HFD) that led to obvious lipid accumulation, which can be propagated their progeny. Using this model, we discovered that transcription factors DAF-16/FOXO and SBP-1, nuclear receptors NHR-49 and NHR-80, and delta-9 desaturase (fat-5, fat-6, and fat-7) are required for transgenerational fat accumulation. Additionally, histone H3K4 tri-methylation (H3K4me3) marks genes related to lipid metabolism and increases their transcription response to multigenerational obesogenic effects. In summary, this study establishes that a network of lipid metabolic genes and chromatin modifications work together to achieve multigenerational obesogenic effects.

Plasma Oleic-to-Stearic Acid Ratio and Future Heart Failure Risk: From MESA

Objectives Evidence for a role of delta-9-desaturase plasma (D9D) in heart failure (HF) is limited. We aimed to evaluate whether a biomarker for its activity, the oleic-to-stearic acid ratio, is associated with future heart failure risk in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. Methods A total of 6562 participants aged 45 to 84 yr. old had their fatty acids measured at baseline. Cox regression was used to model the association between oleic-to-stearic acid ratio and risk for HF, including HF with reduced ejection fraction (EF) and HF with preserved EF, adjusting for potential covariates, including age, sex, race, study center, body mass index, diabetes mellitus, blood pressure, C-reactive protein, albuminuria, and lead fatty acid for non-oleic and non-stearic acid clusters. Mediation effects through hypertension, and diabetes were estimated using the causal mediation analysis. Results After a median of 7.1 years follow-up, 184 incident HF cases were documented, with 64 HF with reduced EF, and 72 HF with preserved EF and 48 with unknown EF status. Oleic-to-stearic acid ratio was lower in HF-free participants (0.57 ± 0.13) compared to participants with HF (0.60 ± 0.12) (P = 0.002) and was associated with a higher risk for HF incidence. Hazard ratio for HF was 4.81 (95%Confidence Interval: 1.46, 15.88) per unit increase in oleic-to-stearic ratio in the fully adjusted model. Secondary analysis showed no dependence on HF type. Mediation analysis showed hypertension and diabetes were not mediating. Conclusions This study indicates that increased delta-9-desaturase activity predicts future HF risk, in a manner not mediated by either hypertension or diabetes. Funding Sources This work was funded by grant from the National Heart, Lung, and Blood Institute.

3-O-Methyl-Alkylgallates Inhibit Fatty Acid Desaturation inMycobacterium tuberculosis

ABSTRACTIn the quest for new antibacterial lead structures, activity screening againstMycobacterium tuberculosisidentified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoeLoranthus micranthus. Structure-activity relationship studies indicated that 3-O-methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms showed the strongest growth inhibitionin vitroagainstM. tuberculosis, with a MIC of 6.25 μM. Furthermore, the most active compounds (3-O-methyl-butyl-, 3-O-methyl-hexylgallate, and 3-O-methyl-octylgallate) were devoid of cytotoxicity against various human cell lines. Furthermore, 3-O-methyl-butylgallate showed favorable absorption, distribution, metabolism, and excretion (ADME) criteria, with aPappof 6.2 × 10−6 cm/s, and it did not inhibit P-glycoprotein (P-gp), CYP1A2, CYP2B6 or CYP3A4. Whole-genome sequencing of spontaneous resistant mutants indicated that the compounds target the stearoyl-coenzyme A (stearoyl-CoA) delta-9 desaturase DesA3 and thereby inhibit oleic acid synthesis. Supplementation assays demonstrated that oleic acid addition to the culture medium antagonizes the inhibitory properties of gallic acid derivatives and that sodium salts of saturated palmitic and stearic acid did not show compensatory effects. The moderate bactericidal effect of 3-O-methyl-butylgallate in monotreatment was synergistically enhanced in combination treatment with isoniazid, leading to sterilization in liquid culture.

Overexpression of OLE1 Enhances Cytoplasmic Membrane Stability and Confers Resistance to Cadmium in Saccharomyces cerevisiae

ABSTRACT The heavy metal cadmium is widely used and released into the environment, posing a severe threat to crops and humans. Saccharomyces cerevisiae is one of the most commonly used organisms in the investigation of environmental metal toxicity. We investigated cadmium stress and the adaptive mechanisms of yeast by screening a genome-wide essential gene overexpression library. A candidate gene, OLE1, encodes a delta-9 desaturase and was associated with high anti-cadmium-stress activity. The results demonstrated that the expression of OLE1 was positively correlated with cadmium stress tolerance and induction was independent of Mga2p and Spt23p (important regulatory factors for OLE1). Moreover, in response to cadmium stress, cellular levels of monounsaturated fatty acids were increased. The addition of exogenous unsaturated fatty acids simulated overexpression of OLE1, leading to cadmium resistance. Such regulation of OLE1 in the synthesis of unsaturated fatty acids may serve as a positive feedback mechanism to help cells counter the lipid peroxidation and cytoplasmic membrane damage caused by cadmium. IMPORTANCE A S. cerevisiae gene encoding a delta-9 desaturase, OLE1, was associated with high anti-cadmium-stress activity. The data suggest that the regulation of OLE1 in the synthesis of unsaturated fatty acids may serve as a positive feedback mechanism to help yeast cells counter the lipid peroxidation and cytoplasmic membrane damage caused by cadmium. The discovery of OLE1 involvement in membrane stability may indicate a novel defense strategy against cadmium stress.