Peroxin FgPEX22-Like Is Involved in FgPEX4 Tethering and Fusarium graminearum Pathogenicity

Peroxisomes are essential organelles that play important roles in a variety of biological processes in eukaryotic cells. To understand the synthesis of peroxisomes comprehensively, we identified the gene FgPEX22-like, encoding FgPEX22-like, a peroxin, in Fusarium graminearum. Our results showed that although FgPEX22-like was notably different from other peroxins (PEX) in Saccharomyces cerevisiae, it contained a predicted PEX4-binding site and interacted with FgPEX4 as a rivet protein of FgPEX4. To functionally characterize the roles of FgPEX22-like in F. graminearum, we performed homologous recombination to construct a deletion mutant (ΔPEX22-like). Analysis of the mutant showed that FgPEX22-like was essential for sexual and asexual reproduction, fatty acid utilization, pathogenicity, and production of the mycotoxin deoxynivalenol. Deletion of FgPEX22-like also led to increased production of lipid droplets and decreased elimination of reactive oxygen species. In addition, FgPEX22-like was required for the biogenesis of Woronin bodies. Taken together, our data demonstrate that FgPEX22-like is a peroxin in F. graminearum that interacts with PEX4 by anchoring PEX4 at the peroxisomal membrane and contributes to the peroxisome function in F. graminearum.

Inhibition of Fatty Acid Metabolism Increases EPA and DHA Levels and Protects against Myocardial Ischaemia-Reperfusion Injury in Zucker Rats

Long-chain ω-3 polyunsaturated fatty acids (PUFAs) are known to induce cardiometabolic benefits, but the metabolic pathways of their biosynthesis ensuring sufficient bioavailability require further investigation. Here, we show that a pharmacological decrease in overall fatty acid utilization promotes an increase in the levels of PUFAs and attenuates cardiometabolic disturbances in a Zucker rat metabolic syndrome model. Metabolome analysis showed that inhibition of fatty acid utilization by methyl-GBB increased the concentration of PUFAs but not the total fatty acid levels in plasma. Insulin sensitivity was improved, and the plasma insulin concentration was decreased. Overall, pharmacological modulation of fatty acid handling preserved cardiac glucose and pyruvate oxidation, protected mitochondrial functionality by decreasing long-chain acylcarnitine levels, and decreased myocardial infarct size twofold. Our work shows that partial pharmacological inhibition of fatty acid oxidation is a novel approach to selectively increase the levels of PUFAs and modulate lipid handling to prevent cardiometabolic disturbances.

A longitudinal study of the antilipolytic effect of insulin in women following bariatric surgery

Insulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state.

Advances in Understanding of the Role of Lipid Metabolism in Aging

During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer’s disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.

Metabolism of Gluconeogenic Substrates by an Intracellular Fungal Pathogen Circumvents Nutritional Limitations within Macrophages

ABSTRACT Microbial pathogens exploit host nutrients to proliferate and cause disease. Intracellular pathogens, particularly those exclusively living in the phagosome such as Histoplasma capsulatum, must adapt and acquire nutrients within the nutrient-limited phagosomal environment. In this study, we investigated which host nutrients could be utilized by Histoplasma as carbon sources to proliferate within macrophages. Histoplasma yeasts can grow on hexoses and amino acids but not fatty acids as the carbon source in vitro. Transcriptional analysis and metabolism profiling showed that Histoplasma yeasts downregulate glycolysis and fatty acid utilization but upregulate gluconeogenesis within macrophages. Depletion of glycolysis or fatty acid utilization pathways does not prevent Histoplasma growth within macrophages or impair virulence in vivo. However, loss of function in Pck1, the enzyme catalyzing the first committed step of gluconeogenesis, impairs Histoplasma growth within macrophages and severely attenuates virulence in vivo, indicating that Histoplasma yeasts rely on catabolism of gluconeogenic substrates (e.g., amino acids) to proliferate within macrophages. IMPORTANCE Histoplasma is a primary human fungal pathogen that survives and proliferates within host immune cells, particularly within the macrophage phagosome compartment. The phagosome compartment is a nutrient-limited environment, requiring Histoplasma yeasts to be able to assimilate available carbon sources within the phagosome to meet their nutritional needs. In this study, we showed that Histoplasma yeasts do not utilize fatty acids or hexoses for growth within macrophages. Instead, Histoplasma yeasts consume gluconeogenic substrates to proliferate in macrophages. These findings reveal the phagosome composition from a nutrient standpoint and highlight essential metabolic pathways that are required for a phagosomal pathogen to proliferate in this intracellular environment.

In vitro and in vivo evidence of bioenergetic metabolism alteration by mono-(2-ethylhexyl) phthalate

Background: To better understand the potential alteration of muscle bioenergetic metabolism by the obesogenic toxicant mono-(2ethylhexyl) phthalate (MEHP) the objectives of this research were to determine the: 1) association between urinary MEHP levels and plasma fatty acid levels in women with obesity who participated in National Health and Nutrition Examination Survey (NHANES) studies, and 2) in vitro effects of MEHP on fatty acid, or glucose supported mitochondrial energetics in C2C12 muscle cells.Results: The association between urinary MEHP from NHANES participants with plasma fatty acid levels was studied via secondary data statistical analyses. 14C-palmitic acid oxidation, Seahorse fatty acid oxidation and glycolysis stress tests and western blot analyses were conducted on C2C12 cells exposed to increasing MEHP concentrations. Increased urinary MEHP in women with obesity was associated with increased plasma gamma-linolenic and arachidonic acid levels. C2C12 myotubes exposed to increasing MEHP concentrations, displayed decreased fatty acid oxidation and mitochondrial bioenergetics. Acyl-CoA synthetase long chain 5 (ACSL5) protein level was also upregulated with increasing MEHP exposure in C2C12 myoblasts. Glycolysis was not significantly modified with increased exposure of C2C12 cells to MEHP.Conclusions: MEHP exposure may alter fatty acid utilization at the whole-body level in women with obesity and fatty acid utilization in muscle cells. Our findings are consistent with the idea that women with obesity may be particularly susceptible to the effects of MEHP, which alters fatty acid metabolism in muscle cells.