Browsing by Subject "Fatty Acids"

Now showing 1 - 9 of 9

Open Access
A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report.
(Orphanet J Rare Dis, 2010-10-05) Dessein, Anne-Frédérique; Fontaine, Monique; Andresen, Brage S; Gregersen, Niels; Brivet, Michèle; Rabier, Daniel; Napuri-Gouel, Silvia; Dobbelaere, Dries; Mention-Mulliez, Karine; Martin-Ponthieu, Annie; Briand, Gilbert; Millington, David S; Vianey-Saban, Christine; Wanders, Ronald JA; Vamecq, Joseph
A female patient, with normal familial history, developed at the age of 30 months an episode of diarrhoea, vomiting and lethargy which resolved spontaneously. At the age of 3 years, the patient re-iterated vomiting, was sub-febrile and hypoglycemic, fell into coma, developed seizures and sequels involving right hemi-body. Urinary excretion of hexanoylglycine and suberylglycine was low during this metabolic decompensation. A study of pre- and post-prandial blood glucose and ketones over a period of 24 hours showed a normal glycaemic cycle but a failure to form ketones after 12 hours fasting, suggesting a mitochondrial β-oxidation defect. Total blood carnitine was lowered with unesterified carnitine being half of the lowest control value. A diagnosis of mild MCAD deficiency (MCADD) was based on rates of 1-14C-octanoate and 9, 10-3H-myristate oxidation and of octanoyl-CoA dehydrogenase being reduced to 25% of control values. Other mitochondrial fatty acid oxidation proteins were functionally normal. De novo acylcarnitine synthesis in whole blood samples incubated with deuterated palmitate was also typical of MCADD. Genetic studies showed that the patient was compound heterozygous with a sequence variation in both of the two ACADM alleles; one had the common c.985A>G mutation and the other had a novel c.145C>G mutation. This is the first report for the ACADM gene c.145C>G mutation: it is located in exon 3 and causes a replacement of glutamine to glutamate at position 24 of the mature protein (Q24E). Associated with heterozygosity for c.985A>G mutation, this mutation is responsible for a mild MCADD phenotype along with a clinical story corroborating the emerging literature view that patients with genotypes representing mild MCADD (high residual enzyme activity and low urinary levels of glycine conjugates), similar to some of the mild MCADDs detected by MS/MS newborn screening, may be at risk for disease presentation.
Open Access
Effects of Proximal Tubule Angiotensin II Signaling on Energy Metabolism in the Kidney
(2017-12-12) Jimenez Contreras, Fabian
Chronic kidney disease (CKD) affects over 26 million adults in the United States, thus it is imperative that we deduce more about the pathogenesis of the disease. CKD is generally multi-factorial, and loss of renal function can result from a number of diseases and pathologic processes. For example, propagation of kidney injury and renal fibrosis can result from abnormal regulation of energy metabolism in kidney cells. In renal proximal tubule epithelial cells, a key segment of the nephron, fatty acids are a major fuel source. As the proximal tubule is responsible for the bulk of sodium reabsorption by the kidney, maintaining adequate energy balance is crucial to this function; therefore, alterations in fatty acid oxidation in the renal proximal tubule may lead to renal dysfunction. Our hypothesis is that angiotensin II (Ang II) signaling, a major effector of the powerful renin-angiotensin system (RAS), alters fatty acid oxidation and this becomes exaggerated in states of renal injury such as hypertension and diabetes where the RAS can be dysregulated. Therefore, we sought to explore the metabolic changes linked to Ang II signaling in the renal proximal tubule. Increased levels of Ang II have previously been shown to induce renal fibrosis and hypertension. For our studies, we used a novel mouse line, one lacking AT1a receptors in renal proximal tubule cells (PTKO mice) and expected that the lack of AT1a receptors helps to maintain normal fatty acid oxidation in disease states. To model pathology which might stress the renal proximal tubule cells, we induced two diseases: hypertension, by infusing Ang II via osmotic mini pumps and diabetes, by employing a genetic model of type 1 diabetes, the Akita model. Our major outcome was the assessment of gene expression of several key metabolic pathways, using a quantitative PCR analysis of samples from mouse renal cortex, which is rich in proximal tubules. We aimed to measure genetic biomarkers in the fatty acid oxidation pathway, glucose oxidation pathway, markers of renal injury and fibrosis. These studies demonstrate how two clinically-relevant diseases influence metabolism in the kidney and how leveraging the RAS may lead to solutions against this disruption, and potentially alter CKD progression.
Open Access
Fatty acid composition of wild anthropoid primate milks.
(Comp Biochem Physiol B Biochem Mol Biol, 2008-01) Milligan, Lauren A; Rapoport, Stanley I; Cranfield, Michael R; Dittus, Wolfgang; Glander, Kenneth E; Oftedal, Olav T; Power, Michael L; Whittier, Christopher A; Bazinet, Richard P
Fatty acids in milk reflect the interplay between species-specific physiological mechanisms and maternal diet. Anthropoid primates (apes, Old and New World monkeys) vary in patterns of growth and development and dietary strategies. Milk fatty acid profiles also are predicted to vary widely. This study investigates milk fatty acid composition of five wild anthropoids (Alouatta palliata, Callithrix jacchus, Gorilla beringei beringei, Leontopithecus rosalia, Macaca sinica) to test the null hypothesis of a generalized anthropoid milk fatty acid composition. Milk from New and Old World monkeys had significantly more 8:0 and 10:0 than milk from apes. The leaf eating species G. b. beringei and A. paliatta had a significantly higher proportion of milk 18:3n-3, a fatty acid found primarily in plant lipids. Mean percent composition of 22:6n-3 was significantly different among monkeys and apes, but was similar to the lowest reported values for human milk. Mountain gorillas were unique among anthropoids in the high proportion of milk 20:4n-6. This seems to be unrelated to requirements of a larger brain and may instead reflect species-specific metabolic processes or an unknown source of this fatty acid in the mountain gorilla diet.
Open Access
Metabolic factors associated with incident fracture among older adults with type 2 diabetes mellitus: a nested case-control study.
(Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2023-07) Lee, Richard H; Bain, James; Muehlbauer, Michael; Ilkayeva, Olga; Pieper, Carl; Wixted, Doug; Colón-Emeric, Cathleen
Older adults with type 2 diabetes mellitus have an increased risk of fracture despite a paradoxically higher average bone mineral density. This study identified additional markers of fracture risk in this at-risk population. Non-esterified fatty acids and the amino acids glutamine/glutamate and asparagine/aspartate were associated with incident fractures.
Purpose
Type 2 diabetes mellitus (T2D) is associated with an increased risk of fracture despite a paradoxically higher bone mineral density. Additional markers of fracture risk are needed to identify at-risk individuals.
Method
The MURDOCK study is an ongoing study, initiated in 2007, of residents in central North Carolina. At enrollment, participants completed health questionnaires and provided biospecimen samples. In this nested case-control analysis, incident fractures among adults with T2D, age ≥ 50 years, were identified by self-report and electronic medical record query. Fracture cases were matched 1:2 by age, gender, race/ethnicity, and BMI to those without incident fracture. Stored sera were analyzed for conventional metabolites and targeted metabolomics (amino acids and acylcarnitines). The association between incident fracture and metabolic profile was assessed using conditional logistic regression, controlled for multiple confounders including tobacco and alcohol use, medical comorbidities, and medications.
Results
107 incident fractures were identified with 210 matched controls. Targeted metabolomics analysis included 2 amino acid factors, consisting of: 1) the branched chain amino acids, phenylalanine and tyrosine; and 2) glutamine/glutamate, asparagine/aspartate, arginine, and serine [E/QD/NRS]. After controlling for multiple risk factors, E/QD/NRS was significantly associated with incident fracture (OR 2.50, 95% CI: 1.36-4.63). Non-esterified fatty acids were associated with lower odds of fracture (OR 0.17, 95% CI: 0.03-0.87). There were no associations with fracture among other conventional metabolites, acylcarnitine factors, nor the other amino acid factors.
Conclusion
Our results indicate novel biomarkers, and suggest potential mechanisms, of fracture risk among older adults with T2D.
Open Access
Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress.
(Dis Model Mech, 2010-09) Cho, Kyoung-in; Yi, Haiqing; Tserentsoodol, Nomingerel; Searle, Kelly; Ferreira, Paulo A
Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.
Open Access
Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension.
(J Cell Biol, 1994-02) Patterson, SI; Skene, JH
In neuronal growth cones, the advancing tips of elongating axons and dendrites, specific protein substrates appear to undergo cycles of posttranslational modification by covalent attachment and removal of long-chain fatty acids. We show here that ongoing fatty acylation can be inhibited selectively by long-chain homologues of the antibiotic tunicamycin, a known inhibitor of N-linked glycosylation. Tunicamycin directly inhibits transfer of palmitate to protein in a cell-free system, indicating that tunicamycin inhibition of protein palmitoylation reflects an action of the drug separate from its previously established effects on glycosylation. Tunicamycin treatment of differentiated PC12 cells or dissociated rat sensory neurons, under conditions in which protein palmitoylation is inhibited, produces a prompt cessation of neurite elongation and induces a collapse of neuronal growth cones. These growth cone responses are rapidly reversed by washout of the antibiotic, even in the absence of protein synthesis, or by addition of serum. Two additional lines of evidence suggest that the effects of tunicamycin on growth cones arise from its ability to inhibit protein long-chain acylation, rather than its previously established effects on protein glycosylation and synthesis. (a) The abilities of different tunicamycin homologues to induce growth cone collapse very systematically with the length of the fatty acyl side-chain of tunicamycin, in a manner predicted and observed for the inhibition of protein palmitoylation. Homologues with fatty acyl moieties shorter than palmitic acid (16 hydrocarbons), including potent inhibitors of glycosylation, are poor inhibitors of growth cone function. (b) The tunicamycin-induced impairment of growth cone function can be reversed by the addition of excess exogenous fatty acid, which reverses the inhibition of protein palmitoylation but has no effect on the inhibition of protein glycosylation. These results suggest an important role for dynamic protein acylation in growth cone-mediated extension of neuronal processes.
Open Access
Of fruits and fats: high-sugar diets restore fatty acid profiles in the white adipose tissue of captive dwarf lemurs.
(Proceedings. Biological sciences, 2022-06) Blanco, MB; Greene, LK; Ellsaesser, LN; Schopler, B; Davison, M; Ostrowski, C; Klopfer, PH; Fietz, J; Ehmke, EE
Fat-storing hibernators rely on fatty acids from white adipose tissue (WAT) as an energy source to sustain hibernation. Whereas arctic and temperate hibernators preferentially recruit dietary polyunsaturated fatty acids (PUFAs), tropical hibernators can rely on monounsaturated fatty acids that produce fewer lipid peroxides during oxidation. Nevertheless, compositional data on WAT from tropical hibernators are scant and questions remain regarding fat recruitment and metabolism under different environmental conditions. We analyse fatty acid profiles from the WAT of captive dwarf lemurs (Cheirogaleus medius) subjected to high-sugar or high-fat diets during fattening and cold or warm conditions during hibernation. Dwarf lemurs fed high-sugar (compared to high-fat) diets displayed WAT profiles more comparable to wild lemurs that fatten on fruits and better depleted their fat reserves during hibernation. One PUFA, linoleic acid, remained elevated before hibernation, potentially lingering from the diets provisioned prior to fattening. That dwarf lemurs preferentially recruit the PUFA linoleic acid from diets that are naturally low in availability could explain the discrepancy between captive and wild lemurs' WAT. While demonstrating that minor dietary changes can produce major changes in seasonal fat deposition and depletion, our results highlight the complex role for PUFA metabolism in the ecology of tropical hibernators.
Open Access
Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization.
(Immunity, 2018-01) Zhao, Fei; Xiao, Christine; Evans, Kathy S; Theivanthiran, Tbalamayooran; DeVito, Nicholas; Holtzhausen, Alisha; Liu, Juan; Liu, Xiaojing; Boczkowski, David; Nair, Smita; Locasale, Jason W; Hanks, Brent A
Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.
Open Access
Posttranslational membrane attachment and dynamic fatty acylation of a neuronal growth cone protein, GAP-43.
(The Journal of cell biology, 1989-02) Skene, JH; Virág, I
Growth cones, the motile apparatus at the ends of elongating axons, are sites of extensive and dynamic membrane-cytoskeletal interaction and insertion of new membrane into the growing axon. One of the most abundant proteins in growth cone membranes is a protein designated GAP-43, whose synthesis increases dramatically in most neurons during periods of axon development or regeneration. We have begun to explore the role of GAP-43 in growth cone membrane functions by asking how the protein interacts with those membranes. Membrane-washing experiments indicate that mature GAP-43 is tightly bound to growth cone membranes, and partitioning of Triton X-114-solubilized GAP-43 between detergent-enriched and detergent-depleted phases indicates considerable hydrophobicity. The hydrophobic behavior of the protein is modulated by divalent cations, particularly zinc and calcium. In vivo labeling of GAP-43 in neonatal rat brain with [35S]methionine shows that GAP-43 is initially synthesized as a soluble protein that becomes attached to membranes posttranslationally. In tissue culture, both rat cerebral cortex cells and neuron-like PC12 cells actively incorporate [3H]palmitic acid into GAP-43. Isolated growth cones detached from their cell bodies also incorporate labeled fatty acid into GAP-43, suggesting active turnover of the fatty acid moieties on the mature protein. Hydrolysis of ester-like bonds with neutral hydroxylamine removes the bound fatty acid and exposes new thiol groups on GAP-43, suggesting that fatty acid is attached to the protein's only two cysteine residues, located in a short hydrophobic domain at the amino terminus. Modulation of the protein's hydrophobic behavior by divalent cations suggests that other domains, containing large numbers of negatively charged residues, might also contribute to GAP-43-membrane interactions. Our observations suggest a dynamic and reversible interaction of GAP-43 with growth cone membranes.

Browsing by Subject "Fatty Acids"

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