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International Journal of Molecular... Mar 2022Non-alcoholic fatty liver disease is a pathology with a hard-to-detect onset and is estimated to be present in a quarter of the adult human population. To improve our...
Non-alcoholic fatty liver disease is a pathology with a hard-to-detect onset and is estimated to be present in a quarter of the adult human population. To improve our understanding of the development of non-alcoholic fatty liver disease, we treated a human hepatoma cell line model, HepG2, with increasing concentrations of common fatty acids, namely myristic, palmitic and oleic acid. To reproduce more physiologically representative conditions, we also included combinations of these fatty acids and monitored the cellular response with an in-depth proteomics approach and imaging techniques. The two saturated fatty acids initially presented a similar phenotype of a dose-dependent decrease in growth rates and impaired lipid droplet formation. Detailed analysis revealed that the drop in the growth rates was due to delayed cell-cycle progression following myristic acid treatment, whereas palmitic acid led to cellular apoptosis. In contrast, oleic acid, as well as saturated fatty acid mixtures with oleic acid, led to a dose-dependent increase in lipid droplet volume without adverse impacts on cell growth. Comparing the effects of harmful single-fatty-acid treatments and the well-tolerated fatty acid mixes on the cellular proteome, we were able to differentiate between fatty-acid-specific cellular responses and likely common lipotoxic denominators.
Topics: Fatty Acids; Fatty Acids, Nonesterified; Hepatocytes; Humans; Non-alcoholic Fatty Liver Disease; Oleic Acid; Palmitic Acid; Proteome
PubMed: 35328776
DOI: 10.3390/ijms23063356 -
Journal of Dairy Science May 2022Modification of milk fat composition might be a desirable method to alter manufacturing characteristics or produce dairy products low in saturated fat that more closely...
Modification of milk fat composition might be a desirable method to alter manufacturing characteristics or produce dairy products low in saturated fat that more closely meet consumer dietary preferences. The aim of this research was to evaluate functional properties of cream obtained from milks with fat composition modified by altering the profile of long-chain fatty acids (FA) absorbed from the intestine. A control and 5 mixtures of long-chain free FA were infused into the abomasum of lactating dairy cows in a 6 × 6 Latin square design with 21-d periods. Treatments were as follows: (1) control (no FA infused), (2) mostly saturated FA (C16:C18 = 0.74), (3) low linoleic palm FA (C16:C18 = 0.73), (4) palm FA (C16:C18 = 0.73), (5) soy FA (C16:C18 = 0.10), and (6) high palmitic soy FA (C16:C18 = 0.73). All treatments included meat solubles and Tween 80 as emulsifiers. Viscosity, overrun, whipping time, foam firmness, and foam stability were evaluated in creams (33% fat). Cream from cows infused with soy FA (treatment 5) had the longest whipping time and lowest overrun, foam stability, viscosity, melting point, firmness, and solid fat content at 5 and 20°C because the fat had the highest unsaturated FA content. Increasing palmitic acid content of soy FA (treatment 6) improved functional variables in cream relative to soy FA alone. Differences among treatments 1 to 4 were less pronounced because of the effect of C18:1 trans in treatments 3 and 4 on milk fat yield and composition. Milk fat from cows infused with palm FA (treatment 4) exhibited comparable or better functionality than control cream. Increased polyunsaturated FA in milk fat resulted in increased amounts of triglyceride (TG) fractions with 28, 30, 38, and 40 carbon numbers, increased oleic acid resulted in increased 50-carbon TG, and higher palmitic and myristic acids resulted in greater 44, 46, and 48 carbon number TG. These TG groups consistently correlated with functional properties of creams from different treatments. Our results indicated that optimal functionality of cream is dependent more on its content of palmitic acid than on unsaturated FA. However, an optimal composition of milk fat for cream functional characteristics might be obtained through nutritional manipulation of diets for dairy cows to deliver an optimal profile of FA.
Topics: Animal Feed; Animals; Carbon; Cattle; Diet; Dietary Supplements; Fatty Acids; Female; Lactation; Milk; Palmitic Acid; Triglycerides
PubMed: 35248374
DOI: 10.3168/jds.2021-21411 -
Brain : a Journal of Neurology Apr 2024The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the...
The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.
Topics: Animals; Female; Humans; Male; ATP-Binding Cassette Transporters; Intellectual Disability; Microcephaly; Movement Disorders; Nervous System Malformations; Neurodevelopmental Disorders; Tremor; Zebrafish; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged
PubMed: 37951597
DOI: 10.1093/brain/awad380 -
International Journal of Molecular... May 2021Bacterial symbionts associated with insects are often involved in host development and ecological adaptation. , a common facultative endosymbiont harbored in pea aphids,...
Bacterial symbionts associated with insects are often involved in host development and ecological adaptation. , a common facultative endosymbiont harbored in pea aphids, improves host fitness and heat tolerance, but studies concerning the nutritional metabolism and impact on the aphid host associated with carrying are limited. In the current study, we showed that -infected aphids had a shorter nymphal developmental time and higher body weight than -free aphids when fed on detached leaves. Genes connecting to fatty acid biosynthesis and elongation were up-regulated in -infected aphids. Specifically, elevated expression of fatty acid synthase 1 () and diacylglycerol-o-acyltransferase 2 () could result in accumulation of myristic acid, palmitic acid, linoleic acid, and arachidic acid in fat bodies. Impairing fatty acid synthesis in -infected pea aphids either by a pharmacological inhibitor or through silencing and expression prolonged the nymphal growth period and decreased the aphid body weight. Conversely, supplementation of myristic acid (C14:0) to these aphids restored their normal development and weight gain. Our results indicated that promoted development and growth of its aphid host through enhancing fatty acid biosynthesis. Our discovery has shed more light on nutritional effects underlying the symbiosis between aphids and facultative endosymbionts.
Topics: Animals; Aphids; Fatty Acids; Host Microbial Interactions; Serratia; Symbiosis
PubMed: 34073039
DOI: 10.3390/ijms22115951 -
BMC Oral Health Nov 2021The oral cavity represents a main entrance of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE-2), neuropilin-1...
BACKGROUND
The oral cavity represents a main entrance of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and transmembrane serine protease 2 (TMPRSS2) are essential for the entry of SARS-CoV-2 to the host cells. Both ACE-2 and NRP-1 receptors and TMPRSS2 have been identified in the oral cavity. However, there is limited knowledge about the impact of periapical lesions and their metabolites on the expression of these critical genes. This study aims to measure the impact of periapical lesions and their unique fatty acids (FAs) metabolites on the expression of the aforementioned genes, in addition to interleukin 6 (IL-6) gene and hence SARS-CoV-2 infection loads can be estimated.
METHODS
Gene expression of ACE-2, NRP-1, TMPRSS2, and IL-6 was performed in periapical lesions in comparison to healthy oral cavity. Since FAs are important immunomodulators required for the lipid synthesis essential for receptors synthesis and viral replication, comparative FAs profiling was determined in oral lesions and healthy pulp tissues using gas chromatography-mass spectrometry (GC-MS). The effect of major identified and unique FAs was tested on mammalian cells known to express ACE-2, NRP-1, and TMPRSS2 genes.
RESULTS
Gene expression analysis indicated that ACE-2, NRP-1, and TMPRSS2 were significantly upregulated in healthy clinical samples compared to oral lesions, while the reverse was true with IL-6 gene expression. Saturated and monounsaturated FAs were the major identified shared and unique FAs, respectively. Major shared FAs included palmitic, stearic and myristic acids with the highest percentage in the healthy oral cavity, while unique FAs included 17-octadecynoic acid in periapical abscess, petroselinic acid and L-lactic acid in periapical granuloma, and 1-nonadecene in the radicular cyst. Computational prediction showed that the binding affinity of identified FAs to ACE-2, TMPRSS2 and S protein were insignificant. Further, FA-treated mammalian cells showed significant overexpression of ACE-2, NRP-1 and TMPRSS2 genes except with L-lactic acid and oleic acid caused downregulation of NRP-1 gene, while 17-octadecynoic acid caused insignificant effect.
CONCLUSION
Collectively, a healthy oral cavity is more susceptible to viral infection when compared to that complicated with periapical lesions. FAs play important role in viral infection and their balance can affect the viral loads. Shifting the balance towards higher levels of palmitic, stearic and 1-nonadecene caused significant upregulation of the aforementioned genes and hence higher viral loads. On the other hand, there is a reverse correlation between inflammation and expression of SARS-CoV-2 receptors. Therefore, a mouth preparation that can reduce the levels of palmitic, stearic and 1-nonadecene, while maintaining an immunomodulatory effect can be employed as a future protection strategy against viral infection.
Topics: Animals; COVID-19; Humans; Mouth; SARS-CoV-2; Viral Load
PubMed: 34749700
DOI: 10.1186/s12903-021-01921-5 -
Molecules (Basel, Switzerland) Nov 2023To disperse fatty acids in aqueous solution, choline, a quaternary ammonium ion, has been used recently. So far, only the self-assembly of myristic acid (MA) in the...
To disperse fatty acids in aqueous solution, choline, a quaternary ammonium ion, has been used recently. So far, only the self-assembly of myristic acid (MA) in the presence of choline hydroxide as a function of the molar ratio has been investigated, and, thus, the current understanding of these fatty acid systems is still limited. We investigated the self-assembly of palmitic acid (PA) in the presence of choline hydroxide (ChOH) as a function of the molar ratio () between ChOH and PA. The self-assemblies were characterized by phase contrast microscopy, cryo-TEM, small-angle X-ray scattering, and H NMR. The ionization state of PA was determined by pH, conductivity, and FT-IR measurements. With increase in , various self-assembled structures, including vesicles, lamellar phase, rigid membranes (large sheets, tubules, cones, and polyhedrals), and micelles, form in the PA/ChOH system, different from those of the MA/ChOH system. The change in induces pH variation and, consequently, a change in the PA ionization state, which, in turn, regulates the molecular interactions, including hydrogen bonding and electrostatic interaction, leading to various self-assemblies. Temperature is an important factor used to tune the self-assembly transitions. The fatty acid choline systems studied here potentially may be applicable in medicine, chemical engineering, and biotechnology.
PubMed: 38005186
DOI: 10.3390/molecules28227463 -
Menthol-based deep eutectic systems as antimicrobial and anti-inflammatory agents for wound healing.European Journal of Pharmaceutical... Mar 2023Effective antimicrobial treatment has been identified as a serious and unmet medical need. Herein, we present a strategy based on deep eutectic systems (DES) to overcome...
Effective antimicrobial treatment has been identified as a serious and unmet medical need. Herein, we present a strategy based on deep eutectic systems (DES) to overcome current limitations, answering the need not only to effectively kill bacterial agents but also to avoid their adhesion and proliferation, which is associated with biofilm formation and have a crucial impact on bacterial virulence. To achieve such a goal, natural deep eutectic systems (NADES) based on menthol (Me) and saturated free fatty acids (FFA) were produced, fully physicochemical characterized, and its bioactive properties were described. The antimicrobial potential of menthol-based NADES with FFA, namely, myristic acid (MA), lauric acid (LA), and stearic acid (SA) were investigated towards a broad panel of microorganisms. The obtained data indicates that NADES possess effective antimicrobial properties towards the Gram-positive bacterial and fungal strains tested. Among the tested formulations, Me:LA at a molar ratio of 4:1 molar was used to carry out a biofilm detachment/removal assay due to is superior microbiological properties. This formulation was able to effectively lead to biofilm removal/dispersion of not only methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans, but also Escherichia coli, without the need of any additional physical force or antibiotic. Furthermore, since microbial invasion and biofilm formation is highly undesired in wound healing, namely in chronic wound healing, the wound healing properties of these eutectic formulations was also investigated. The results suggest that these NADES can cope with microbial invasion and biofilm detachment while not compromising normal keratinocyte proliferation and migration verified in wound healing and epidermis repair, while also contributing to the reduction of cell stress and inflammation via the control of ROS production. In conclusion, these results provide the indication that NADES based on Me and FFA holds great interest as antimicrobial agents for preventive and therapeutic applications in various clinical settings, including wound healing.
Topics: Menthol; Methicillin-Resistant Staphylococcus aureus; Anti-Infective Agents; Anti-Bacterial Agents; Anti-Inflammatory Agents; Wound Healing
PubMed: 36572356
DOI: 10.1016/j.ejps.2022.106368 -
The Journal of Neuroscience : the... Mar 2022α-Synuclein (αS) plays a key role in Parkinson's disease. Although Parkinson's disease is typically "sporadic," inherited αS missense mutations provide crucial...
α-Synuclein (αS) plays a key role in Parkinson's disease. Although Parkinson's disease is typically "sporadic," inherited αS missense mutations provide crucial insights into molecular mechanisms. Here, we examine two clinical mutants, E46K and G51D, which are both in the conserved N-terminus that mediates transient αS-membrane interactions. However, E46K increases and G51D decreases αS-membrane interactions. Previously, we amplified E46K via the 11-residue repeat motifs, creating "3K" (E35K+E46K+E61K). Here, we engineered these motifs to amplify G51D (V40D+G51D+V66D = "3D") and systematically compared E46K/3K versus G51D/3D. We found that G51D increased cytosolic αS in neural cells and 3D aggravates this. G51D, and 3D even more, reduced αS multimer-to-monomer (αS60:αS14) ratio. Both amplified variants caused cellular stress in rat primary neurons and reduced growth in human neuroblastoma cells. Importantly, both 3K- and 3D-induced stress was ameliorated by pharmacologically inhibiting stearoyl-CoA desaturase or by conditioning the cells in palmitic (16:0) or myristic (14:0) acid. SCD inhibition lowered lipid-droplet accumulation in both 3D- and 3K-expressing cells and benefitted G51D by normalizing multimer:monomer ratio, as reported previously for E46K. Our findings suggest that, despite divergent cytosol/membrane partitioning, both G51D and E46K neurotoxicity can be prevented by decreasing fatty-acid unsaturation as a common therapeutic approach. α-Synuclein (αS) dyshomeostasis is linked to Parkinson's disease. Here we focus on two contrasting familial-Parkinson's disease αS mutants, E46K and G51D, that alter αS membrane association in opposite directions (E46K increases, G51D decreases it). Taking advantage of αS repeat structure, here we designed αS "3D," an amplified G51D variant (V40D+G51D+V66D). αS 3D further enhanced G51D's cytosolic enrichment. Systematic comparison of G51D/3D with membrane-enriched E46K/its amplified variant 3K revealed that both can elicit stress in human neural cells and primary rodent neurons. This toxicity can be ameliorated by inhibiting stearoyl-CoA desaturase or by saturated fatty acid conditioning. Thus, despite divergent membrane binding, both G51D and E46K αS dyshomeostasis are mitigated by altering fatty acid saturation as a shared target.
Topics: Animals; Cytosol; Fatty Acids; Homeostasis; Parkinson Disease; Rats; Stearoyl-CoA Desaturase; alpha-Synuclein
PubMed: 35086904
DOI: 10.1523/JNEUROSCI.1881-21.2022 -
ACS Omega May 2022Thermal properties, stability, and reliability of lauric acid-based binary eutectic mixtures for building energy efficiency were studied. The eutectic points and phase...
Thermal properties, stability, and reliability of lauric acid-based binary eutectic mixtures for building energy efficiency were studied. The eutectic points and phase change performance of these binary PCMs were obtained as follows: (1) For lauric acid-myristic acid, the mass eutectic point is 70 wt % LA/30 wt % MA. (2) For lauric acid-palmitic acid, the eutectic point is 79 wt % LA/21 wt % PA. (3) For lauric acid-stearic acid, the eutectic point is 82 wt % LA/18 wt % SA. The eutectic PCMs have a melting enthalpy of 166.18, 183.07, and 189.50 J·g and a melting temperature of 35.10, 37.15, and 39.29 °C for lauric-myristic acid, lauric-palmitic acid, and lauric-stearic acid binary eutectic PCMs, respectively. The experimental results are very close to the theoretical results. Moreover, from FT-IR and XRD investigations, we realized that during the preparation of the lauric acid-based binary eutectic fatty acids, no new functional groups were produced. Besides, the TG illustrated that the LA-MA eutectic PCMs, LA-PA eutectic PCMs, and LA-SA eutectic PCMs exhibit excellent thermal stability below 126.51, 135.7, and 110.08 °C, respectively. Finally, lauric acid-based binary eutectic PCMs still show excellent thermal properties and chemical structure after 500 hot and cold cycles. All in all, as a novel material for building energy conservation, lauric acid-based binary eutectic PCMs have broad prospects and good practicability.
PubMed: 35571813
DOI: 10.1021/acsomega.2c01420 -
The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.The EMBO Journal Feb 2024The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal...
The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1 mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory.
Topics: Animals; Mice; Brain; Fatty Acids, Nonesterified; Memory; Memory, Long-Term; Munc18 Proteins; Phospholipases
PubMed: 38316990
DOI: 10.1038/s44318-024-00030-7