Biology subjects

Brenna, J. T.

Publications and source records attributed to Brenna, J. T..

9 recordsLinked to original sources

bioRxiv2024

High dose ω3 eicosapentaenoic acid and docosahexaenoic acid block, whereas ω6 arachidonic acid accelerates, MYCN-driven tumorigenesis in vivo

Background/ObjectivesNeuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood cancer deaths despite only having ~8% of childhood cancer incidence. The current standard of care for high-risk disease is highly genotoxic. This, combined with less than 50% survival in high-risk disease and an abysmal 5% survival in relapsed cases, makes discovering novel, effective, and less toxic treatments essential. MethodsA prophylactic syngeneic mouse model was used to test high-dose lipid-mediator highly unsaturated fatty acids on tumorigenesis. Wild-type mice were gavaged with 12.3-14.6 g/d (adult human equivalent) omega-3 EPA, DHA, or oxidation-resistant bis allylic deuterated DHA (D-DHA) and 4.6-6.0 g/d arachidonic acid (ARA). At seven days, MYCN-expressing murine neuro-2a cells syngeneic to the gavaged mice were injected subcutaneously. Oral gavage continued for 10-20 d post-injection when tumors and tissues were harvested. ResultsFifty percent of control (not gavaged) animals form tumors (4/8) at about 10 d. High-dose DHA, D-DHA, and EPA block tumor formation completely in n=8 or 10 animals. In contrast, {omega}6 arachidonic acid (4.6-6.0 g/d) enhances tumor formation (6/10 tumors) and reduces latency (5.5 to 10 days)compared to control. Co-delivery of ARA and EPA results in a reduced tumor burden analogous to the control group, suggesting that EPA directly opposes the mechanism of ARA-mediated tumor formation. DHA acts through a non-oxidative mechanism. ConclusionsSustained high dose {omega}3 (weeks/months) is safe and well tolerated in humans. These results suggest that {omega}3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma. Simple SummaryPediatric Neuroblastoma has an overall mortality rate above 50%, and the current standard of care consists of highly genotoxic compounds. The biological actions of omega-6 ({omega}6) and omega-3 ({omega}3) highly unsaturated fatty acids (HUFA) generally oppose one another with the {omega}6 HUFA signaling for inflammation and angiogenesis (new blood vessel formation). Prolonged use of ultrahigh dose (15-20 g/d) {omega}3 HUFA has shown efficacy in catastrophic human traumatic brain injury and is well tolerated. Tumors form in about 50% of mice in our pediatric neuro-blastoma model. We show that 12-14 g/d adult human equivalent doses of {omega}3 EPA or DHA, as well as an oxidation-resistant form of DHA (D-DHA), completely block tumor formation, whereas a dose of about 5 g/d of {omega}6 ARA enhances tumorigenesis. Our data suggest that ultra-high dose {omega}3 therapy should be carefully investigated as a low-toxicity approach to neuroblastoma intervention.

cancer biology↗

bioRxiv2023

Unsaturated fatty acid synthesis is associated with poor prognosis in pediatric neuroblastoma and is differentially regulated by MYCN and tumor suppressor microRNAs.

MYCN amplification and disruption of tumor suppressor microRNA (TSmiR) function are central drivers of poor outcomes in neuroblastoma (NB). MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in unsaturated fatty acid synthesis (UFAS) remains poorly understood. Here we show that de novo and UFAS pathway genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. In addition, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, NB cells are high in omega 9 ({omega}9) unsaturated fatty acids that can be synthesized de novo and low in both {omega}6 and {omega}3, providing a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from {omega}6 and {omega}3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC-driven cancers.

cancer biology↗

bioRxiv2022

Remodeling of gene regulatory networks underlying thermogenic stimuli-induced adipose beiging

Beige adipocytes are induced by cold temperatures or {beta}3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the two stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify the unique functional consequences of manipulating these pathways in vivo.

genomics↗

bioRxiv2021

Evaluation of the Efficacy of Omega-3 Fatty Acids Formulations in the Lipopolysaccharide-Induced Acute Lung Inflammation Rat Model

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. The O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour later, rats received nebulized treatments consisting of egg lecithin emulsified O3, budesonide and Montelukast, and blends of O3 and melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n=3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-, TGF-{beta}, and IL-10 were attenuated in all O3 groups. IL-1{beta} was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress like COVID-19.

physiology↗

bioRxiv2021

Single-cell Chromatin Accessibility and Lipid Profiling Reveals a Metabolic Shift in Adipocytes Induced by Bariatric Surgery

Obesity promotes type 2 diabetes and cardiometabolic pathologies. Vertical sleeve gastrectomy (VSG) is used to treat obesity resulting in long-term weight loss and health improvements that precede weight loss; however, the mechanisms underlying the immediate benefits remain incompletely understood. Because adipose plays a crucial role in energy homeostasis and utilization, we hypothesized that VSG exerts its influences, in part, by modulating adipose functional states. We applied single-cell ATAC sequencing and lipid profiling to inguinal and epididymal adipose depots from mice that received sham surgery or VSG. We observed depot-specific cellular composition and chromatin accessibility patterns that were altered by VSG. Specifically, accessibility at Scd1, a fatty acid desaturase, was substantially reduced after VSG in mature adipocytes of inguinal but not epididymal depots. This was accompanied by reduced accumulation of SCD1-produced unsaturated fatty acids. Given these findings and reports that reductions in Scd1 attenuate obesity and insulin resistance and that unsaturated fatty acids stimulate glucose uptake, storage, and oxidation, our results suggest VSG exerts its beneficial effects through modifications of fatty acid profiles mediated by Scd1.

genomics↗

bioRxiv2021

LRH-1 NUTRIGENOMICS: The Provision of Lauric Acid Results in the Endogenous Production of the Liver Receptor Homolog-1 Ligand, Dilauroylphosphatidylcholine, and LRH-1 Transactivation

BackgroundThe unusual phosphatidylcholine species, dilauroylphosphatidylcholine (DLPC), has been reported to bind and activate the orphan nuclear receptor, liver receptor homolog-1 (LRH-1). To date, DLPC has not been reported endogenously in metabolomic databases. ObjectiveHerein, we test the hypothesis that the provision of the acyl constituent of DLPC, lauric acid (C12:0), a saturated fatty acid rich in tropical oils such as coconut oil, will 1) result in endogenous DLPC production and 2) enhance LRH-1 transcriptional activity. MethodsWe measured DLPC following provision of C12:0 to HepG2 cells, C57/BL6J mice, and to healthy human participants in an acute, randomized, controlled cross-over trial. LRH-1fl/fl and LRH-1fl/fl Albumin-Cre mice were used in ex vivo and in vivo approaches. to assess the impact of C12:0 on LRH-1 target gene expression. 1-13C-lauric acid and methyl-d9-choline were used to assess DLPC production dynamics. ResultsDLPC was not observed in any C12:0-free approach. Provision of C12:0 in the culture media or to C57/BL6J mice resulted in the rapid production of DLPC, including DLPCs presence in multiple LRH-1 expressing tissues. Coconut oil-fed human participants exhibited DLPC in postprandial serum samples. Ex vivo and in vivo C12:0 provision resulted in increased mRNA expression of LRH-1 target genes, an effect that was not observed in hepatic knockout mice. Methyl-d9-choline administration revealed a complex reliance on CDP-choline-derived DLPC. ConclusionC12:0 provision results in endogenous production of the LRH-1 ligand, DLPC, and LRH-1 transcriptional activation phenotypes. Our findings highlight pleiotropic effects of lauric acid, a common hypercholesterolemic dietary saturated fatty acid, secondary to LRH-1 agonism.

physiology↗

bioRxiv2020

The microbiome affects liver sphingolipids and plasma fatty acids in a murine model of the Western diet based on soybean oil

Studies in mice using germfree animals as controls for microbial colonization have shown that the gut microbiome mediates diet-induced obesity. Such studies use diets rich in saturated fat, however, Western diets in the USA are enriched in soybean oil, composed of unsaturated fatty acids (FAs), either linoleic or oleic acid. Here we addressed whether the microbiome is a variable in fat metabolism in mice on a soybean oil diet. We used conventionally-raised, low-germ, and germfree mice fed for 10 weeks diets either high (HF) or low (LF) in high-linoleic-acid soybean oil as the sole source of fat. All mice, including germfree, gained relative fat weight and consumed more calories on the HF versus LF soybean oil diet. Plasma fatty acid levels were generally dependent on diet, with microbial colonization status affecting iso-C18:0, C20:3n-6, C14:0, and C15:0 levels. Colonization status, but not diet, impacted levels of liver sphingolipids including ceramides, sphingomyelins, and sphinganine. Our results confirm that absorbed fatty acids are mainly a reflection of the diet, and show that microbial colonization influences liver sphingolipid pools.

systems biology↗

bioRxiv2017

Resilience mechanisms of small intestinal lactobacilli to the toxicity of soybean oil fatty acids

Over the past century, soybean oil (SBO) consumption in the United States increased dramatically. The main SBO fatty acid, linoleic acid (18:2), inhibits in vitro the growth of lactobacilli, beneficial members of the small intestinal microbiota. Human-associated lactobacilli have declined in prevalence in Western microbiomes, but how dietary changes may have impacted their ecology is unclear. Here, we compared the in vitro and in vivo effects of 18:2 on Lactobacillus reuteri and L. johnsonii. Directed evolution in vitro in both species led to strong 18:2 resistance with mutations in genes for lipid biosynthesis, acid stress, and the cell membrane or wall. Small-intestinal Lactobacillus populations in mice were unaffected by chronic and acute 18:2 exposure, yet harbored both 18:2- sensitive and resistant strains. This work shows that extant small intestinal lactobacilli are protected from toxic dietary components via the gut environment as well as their own capacity to evolve resistance.

microbiology↗

bioRxiv2017

Taking the short- or long-chain route: conversion efficiency of alpha linolenic acid to long-chain omega-3 fatty acids in aerial insectivore chicks

Food availability and quality are both critical for growing young animals. In nature, swallows (Tachycineta bicolor) and other aerial insectivores feed on both aquatic insects, which are rich in omega-3 long-chain polyunsaturated fatty acid (LCPUFA) and terrestrial insects, which contain considerably less LCPUFA. Carnivorous mammals and fishes must obtain LCPUFA from diet, as they have lost the capacity to convert the precursor omega-3 ALA into LCPUFA. Thus, the relative value of aquatic versus terrestrial insects depends not only on the fatty acid composition of the prey, but also upon the capacity of consumers to convert ALA into LCPUFA. We used a combination of stable-isotope-labeled fatty acid tracers to ask if, and how efficiently, Tree Swallows can deposit newly synthesized LCPUFA into tissue. Our data show for the first time that Tree Swallows can convert ALA into LCPUFA deposited in liver and skeletal muscle. However, high Tree Swallow demand for LCPUFA combined with low ALA availability in natural terrestrial foods may strain their modest conversion ability. This suggests that while Tree Swallows can synthesize LCPUFA de novo, LCPUFA are ecologically essential nutrients in natural systems. Our findings thus provide mechanistic support for our previous findings and the importance of LCPUFA-rich aquatic insects for Tree Swallows and most likely other aerial insectivores with similar niches.\n\nSummary StatementA stable-isotope-labeled tracer reveals the mechanism for omega-3 long-chain polyunsaturated fatty acid (LCPUFA) limitation in a wild avian insectivore, showing that LCPUFA are an ecologically essential nutrient.

ecology↗