Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs.
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ABSTRACT:
SUBMITTER: Khandelwal N
PROVIDER: S-EPMC7611549 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Fatty acid binding and oxidation kinetics for wild type P450(BM3) (CYP102A1) from Bacillus megaterium have been found to display chain length-dependent homotropic behavior. Laurate and 13-methyl-myristate display Michaelis-Menten behavior while there are slight deviations with myristate at low ionic strengths. Palmitate shows Michaelis-Menten kinetics and hyperbolic binding behavior in 100 mmol/L phosphate, pH 7.4, but sigmoidal kinetics (with an apparent intercept) in low ionic strength buffers and at physiological phosphate concentrations. In low ionic strength buffers both the heme domain and the full-length enzyme show complex palmitate binding behavior that indicates a minimum of four fatty acid binding sites, with high cooperativity for the binding of the fourth palmitate molecule, and the full-length enzyme showing tighter palmitate binding than the heme domain. The first flavin-to-heme electron transfer is faster for laurate, myristate and palmitate in 100 mmol/L phosphate than in 50 mmol/L Tris (pH 7.4), yet each substrate induces similar high-spin heme content. For palmitate in low phosphate buffer concentrations, the rate constant of the first electron transfer is much larger than k (cat). The results suggest that phosphate has a specific effect in promoting the first electron transfer step, and that P450(BM3) could modulate Bacillus membrane morphology and fluidity via palmitate oxidation in response to the external phosphate concentration.
| S-EPMC4875328 | biostudies-literature
Project description:Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity influencing acyl-chain diversity in the lipidome.
| S-EPMC6245668 | biostudies-literature
Project description:The number of genes encoding β-oxidation enzymes in Cupriavidus necator H16 (synonym, Ralstonia eutropha H16) is high, but only the operons A0459-A0464 and A1526-A1531, each encoding four genes for β-oxidation enzymes, were expressed during growth with long-chain-length fatty acids (LCFAs). However, we observed that C. necator ΔA0459-A0464 ΔA1526-A1531 and C. necator H16 showed the same growth behavior during growth with decanoic acid and shorter FAs. The negative effect of the deletion of these two operons increased with an increasing chain length of the utilized FAs. Transcriptome sequencing (RNA-Seq) revealed the expression profiles of genes involved in the catabolism of medium-chain-length fatty acids (MCFAs) in C. necator H16. Operon A0459-A0464 was expressed only during growth with nonanoic acid, whereas operon A1526-A1531 was highly expressed during growth with octanoic and nonanoic acid. The gene clusters B1187-B1192 and B0751-B0759 showed a log2 fold change in expression of up to 4.29 and 4.02, respectively, during growth with octanoic acid and up to 8.82 and 5.50, respectively, with nonanoic acid compared to sodium gluconate-grown cells. Several acyl-CoA ligases catalyze the activation of MCFAs with coenzyme A (CoA), but fadD3 (A3288), involved in activation of LCFAs, was not detected. The expression profiles of C. necator strain ΔA0459-A0464 ΔA1526-A1531 showed that the growth with nonanoic acid resulted in the expression of further β-oxidation enzyme-encoding genes. Additional insights into the transport of FAs in C. necator H16 revealed the complexity and putative involvement of the DegV-like protein encoded by A0463 in the transport of odd-chain-length FAs and of siderophore biosynthesis in the transport mechanism. IMPORTANCE Although Cupriavidus necator H16 has been used in several studies to produce polyhydroxyalkanoates from various lipids, the fatty acid metabolism is poorly understood. The β-oxidation of long-chain-length FAs has been investigated, but the tremendous number of homologous genes encoding β-oxidation enzymes hides the potential for variances in the expressed genes for catabolism of shorter FAs. The catabolism of medium-chain-length FAs and connected pathways has not been investigated yet. As more sustainable substrates such as lipids and the production of fatty acids and fatty acid derivates become more critical with the dependency on fossil-based substances, understanding the complex metabolism in this highly diverse workhorse for biotechnology, C. necator, is inevitable. For further metabolic engineering and construction of production strains, we investigated the metabolism during growth on medium-chain-length FAs by RNA-Seq.
| S-EPMC9888253 | biostudies-literature
Project description:Ceramide synthase 2 (CerS2) null mice cannot synthesize very-long acyl chain (C22-C24) ceramides resulting in significant alterations in the acyl chain composition of sphingolipids. We now demonstrate that hepatic triacylglycerol (TG) levels are reduced in the liver but not in the adipose tissue or skeletal muscle of the CerS2 null mouse, both before and after feeding with a high fat diet (HFD), where no weight gain was observed and large hepatic nodules appeared. Uptake of both BODIPY-palmitate and [VH]-palmitate was also abrogated in the hepa- tocytes and liver. The role of a number of key proteins involved in fatty acid uptake was examined, including FATP5, CD36/FAT, FABPpm and cytoplasmic FABP1. Levels of FATP5 and FABP1 were decreased in the CerS2 null mouse liver, whereas CD36/FAT levels were significantly elevated and CD36/FAT was also mislocalized upon insulin treatment. Moreover, treatment of hepatocytes with C22-C24-ceramides down-regulated CD36/FAT levels. Infection of CerS2 null mice with recombinant adeno-associated virus (rAAV)-CerS2 restored normal TG levels and corrected the mislocalization of CD36/FAT, but had no effect on the intracellular localization or levels of FATP5 or FABP1. Together, these results demonstrate that hepatic fatty acid uptake via CD36/FAT can be regulated by altering the acyl chain composition of sphingolipids.
| S-EPMC4406097 | biostudies-literature
Project description:PurposeWe hypothesize that different types of dietary fatty acids (FAs) affect gastrointestinal (GI) motility and visceromotor function and that this effect can be regulated by the fatty acid binding protein 4 (FABP4).MethodsMice were fed for 60 days with standard diet (STD), STD with 7% (by weight) coconut oil, rich in medium-chain FAs (MCFAs) (COCO), or with 7% evening primrose oil, rich in long-chain FAs (LCFAs) (EPO). In each group, half of the mice received FABP4 inhibitor, BMS309403 (1 mg/kg; i.p.) twice a week. Body weight (BW) and food intake were measured; well-established tests were performed to characterize the changes in GI motility and visceral pain. White adipose tissue and colonic samples were collected for cell culturing and molecular studies.ResultsCOCO significantly increased GI transit, but not colonic motility. COCO and EPO delayed the onset of diarrhea, but none affected the effect of loperamide. EPO reduced BW and increased the visceromotor response (VMR) to colorectal distension (CRD). COCO and EPO reduced differentiation of preadipocytes. Treatment with BMS309403: (1) reversed the effects induced by COCO in physiological conditions and in mouse models of diarrhea; (2) prevented the effects of EPO on BW, VMR to CRD and castor oil-induced diarrhea; (3) affected proliferation of preadipocytes; (4) changed the expression of Fabp4 in colonic and adipocyte samples from COCO and EPO.ConclusionModifying dietary intake of MCFAs and LCFAs may be used to control GI motility or visceral pain and thus modulate the symptoms of functional GI disorders. The effect is dependent on the expression of FABP4.
| S-EPMC7413912 | biostudies-literature
Project description:Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1?; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1? to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.
| S-EPMC4949205 | biostudies-literature
Project description:Cardiovascular diseases (CVD) are a leading cause of mortality worldwide, and dietary habits represent a major risk factor for dyslipidemia; a hallmark of CVD. Saturated fatty acids contribute to CVD by aggravating dyslipidemia, and, in particular, lauric acid (LA) raises circulating cholesterol levels. The role of red blood cells (RBCs) in CVD is increasingly being appreciated, and eryptosis has recently been identified as a novel mechanism in CVD. However, the effect of LA on RBC physiology has not been thoroughly investigated. RBCs were isolated from heparin-anticoagulated whole blood (WB) and exposed to 50-250 μM of LA for 24 h at 37 °C. Hemoglobin was photometrically examined as an indicator of hemolysis, whereas eryptosis was assessed by Annexin V-FITC for phosphatidylserine (PS) exposure, Fluo4/AM for Ca2+, light scatter for cellular morphology, H2DCFDA for oxidative stress, and BODIPY 581/591 C11 for lipid peroxidation. WB was also examined for RBC, leukocyte, and platelet viability and indices. LA caused dose-responsive hemolysis, and Ca2+-dependent PS exposure, elevated erythrocyte sedimentation rate (ESR), cytosolic Ca2+ overload, cell shrinkage and granularity, oxidative stress, accumulation of lipid peroxides, and stimulation of casein kinase 1α (CK1α). In WB, LA disrupted leukocyte distribution with elevated neutrophil-lymphocyte ratio (NLR) due to selective toxicity to lymphocytes. In conclusion, this report provides the first evidence of the pro-eryptotic potential of LA and associated mechanisms, which informs dietary interventions aimed at CVD prevention and management.
| S-EPMC8699421 | biostudies-literature
Project description:Despite advances in understanding the metabolism of Pseudomonas putida KT2440, a promising bacterial host for producing valuable chemicals from plant-derived feedstocks, a strain capable of producing free fatty acid-derived chemicals has not been developed. Guided by functional genomics, we engineered P. putida to produce medium- and long-chain free fatty acids (FFAs) to titers of up to 670 mg/L. Additionally, by taking advantage of the varying substrate preferences of paralogous native fatty acyl-CoA ligases, we employed a strategy to control FFA chain length that resulted in a P. putida strain specialized in producing medium-chain FFAs. Finally, we demonstrate the production of oleochemicals in these strains by synthesizing medium-chain fatty acid methyl esters, compounds useful as biodiesel blending agents, in various media including sorghum hydrolysate at titers greater than 300 mg/L. This work paves the road to produce high-value oleochemicals and biofuels from cheap feedstocks, such as plant biomass, using this host.
| S-EPMC9744835 | biostudies-literature
Project description:A requirement for concentrated and chemically homogeneous pools of molecular building blocks would severely restrict plausible scenarios for the origin of life. In the case of membrane self-assembly, models of prebiotic lipid synthesis yield primarily short, single-chain amphiphiles that can form bilayer vesicles only at very high concentrations. These high critical aggregation concentrations (cacs) pose significant obstacles for the self-assembly of single-chain lipid membranes. Here, we examine membrane self-assembly in mixtures of fatty acids with varying chain lengths, an expected feature of any abiotic lipid synthesis. We derive theoretical predictions for the cac of mixtures by adapting thermodynamic models developed for the analogous phenomenon of mixed micelle self-assembly. We then use several complementary methods to characterize aggregation experimentally, and find cac values in close agreement with our theoretical predictions. These measurements establish that the cac of fatty acid mixtures is dramatically lowered by minor fractions of long-chain species, thereby providing a plausible route for protocell membrane assembly. Using an NMR-based approach to monitor aggregation of isotopically labeled samples, we demonstrate the incorporation of individual components into mixed vesicles. These experiments suggest that vesicles assembled in dilute, mixed solutions are depleted of the shorter-chain-length lipid species, a finding that carries implications for the composition of primitive cell membranes.
| S-EPMC4190651 | biostudies-literature
Project description:This transcriptomic study investigates the effect of therapeutic short-chain fatty acids (SCFA) administration on post-stroke recovery.
2020-01-01 | GSE131788 | GEO