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Cell Research Mar 2024Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by...
Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream G signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating G/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a "born to be activated and cold to enhance" model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.
Topics: Animals; Mice; Adipose Tissue, Brown; Cell Membrane; Cryoelectron Microscopy; Ligands; Mice, Knockout; Oleic Acid; Receptors, G-Protein-Coupled
PubMed: 38287117
DOI: 10.1038/s41422-024-00932-5 -
International Journal of Molecular... Aug 2023This study aimed to assess the impact of oleic acid (OA) supplementation on the biosynthesis of 10-hydroxy-2-decenoic acid (10-HDA) in . In experiment 1, varying...
This study aimed to assess the impact of oleic acid (OA) supplementation on the biosynthesis of 10-hydroxy-2-decenoic acid (10-HDA) in . In experiment 1, varying concentrations of OA (2%, 4%, 6% and 8%) were added to an artificial diet for newly emerged bees reared in cages. Analysis of 10-HDA content and gene expression in the mandibular gland (MG) revealed that the 8% OA treatment had the greatest impact on promoting the synthesis of 10-HDA. Subsequent investigations utilized RNA-seq and lipidomics to characterize the molecular signature in the MG after feeding the 8% OA diet. Phosphatidylcholine (PC) and triacylglycerol (TAG) were found to be the predominant lipids in the MG of worker bees. A total of 154 TAGs were identified, with TAG (18:1-18:1-18:1) exhibiting the highest abundance, which increased by 1.5 times. The major TAG species contained palmitic acid (16:0) and oleic acid (18:1) in their structure, which was associated with fatty acid composition of diet. The increase in abundance of main TAGs may be attributed to the upregulation of glycerol-3-phosphate acyltransferase (Gpat) and glycerol kinase (GK) gene expression at the transcriptional level. The upregulation of differentially expressed genes (DEGs) related to carbohydrate metabolism may contribute to meeting the heightened metabolic demands of the MGs in worker bees. Royal jelly (RJ) samples from bee colonies fed with the 8% OA diet exhibited higher 10-HDA level than RJ collected from bee colonies fed with the artificial diet. These results indicate that 8% OA addition in the diet enhanced biosynthesis of 10-HDA in the mandibular gland, which was accompanied by significant and highly species-selective remodeling of TAGs.
Topics: Bees; Animals; Oleic Acid; Fatty Acids, Monounsaturated; Glycerol-3-Phosphate O-Acyltransferase; Lecithins; Triglycerides
PubMed: 37686166
DOI: 10.3390/ijms241713361 -
Applied Biochemistry and Biotechnology Oct 2023The endoplasmic reticulum (ER) resident proteins of the Orm family (Orm1p and Orm2p) play an essential regulatory role in sphingolipid metabolism and proteostasis of...
The endoplasmic reticulum (ER) resident proteins of the Orm family (Orm1p and Orm2p) play an essential regulatory role in sphingolipid metabolism and proteostasis of Saccharomyces cerevisiae. Sphingolipid metabolism and its relationship with yeast ORM1 and ORM2 have been studied widely, but its position in phospholipids and neutral lipids requires further studies. We found that the deletion of ORM2 reduced phospholipid levels, but orm1Δ had shown no significant alteration of phospholipids. On the contrary, neutral lipid levels and lipid droplet (LD) numbers were increased in both orm1∆ and orm2∆ cells. Unlike orm1Δ, free fatty acid (FFA) levels were steeply accumulated in orm2∆ cells, and deletion of ORM2 made the cells more sensitive towards oleic acid toxicity. Misregulation of fatty acids has been implicated in the causation of several lipid metabolic disorders. It is imminent to comprehend the control mechanisms of free fatty acid homeostasis and its pathophysiology. Our study has provided experimental evidence of ORM2 role in the lipid and fatty acid metabolism of yeast.
Topics: Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Oleic Acid; Fatty Acids, Nonesterified; Sphingolipids; Phospholipids; Lipid Metabolism
PubMed: 36719521
DOI: 10.1007/s12010-023-04359-3 -
Frontiers in Immunology 2023Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration.... (Review)
Review
Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells' Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na and K ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology.
Topics: Humans; Lung Injury; Pneumonia; Respiratory Distress Syndrome; Sodium-Potassium-Exchanging ATPase; Edema
PubMed: 38299144
DOI: 10.3389/fimmu.2023.1287512 -
The British Journal of Nutrition Feb 2024The present study investigated the potential role of the composition of dietary fatty acids in the regulation of biological rhythms, such as the sleep architecture, core...
The present study investigated the potential role of the composition of dietary fatty acids in the regulation of biological rhythms, such as the sleep architecture, core body temperature and leukocyte clock gene expression, in subjects fed meals rich in palmitic acid (PA) or oleic acid (OA). Eleven males participated in two sessions of indirect calorimetry in a whole-room metabolic chamber. In each session, subjects consumed three meals rich in PA (44·3 % of total fat as PA and 42·3 % as OA) or OA (11·7 % of total fat as PA and 59·3 % as OA) in the metabolic chamber. The ratio of PA to OA in plasma was significantly lower and fat oxidation was significantly higher during 24 h of indirect calorimetry in the session with meals rich in OA than in that with meals rich in PA. The duration of slow wave sleep (SWS) was shorter, the latency of SWS was longer and the nadir of core body temperature after bedtime was later in the session with meals rich in PA than in that with meals rich in OA. The peak in gene expression was earlier and its amplitude was higher in the session with meals rich in PA than in that with meals rich in OA. In healthy young males, meals rich in PA decreased fat oxidation and disrupted biological rhythms, particularly the sleep architecture and core body temperature during sleep, more than meals rich in OA.
Topics: Male; Humans; Palmitic Acid; Oleic Acid; Japan; Energy Metabolism; Periodicity; Dietary Fats
PubMed: 37578022
DOI: 10.1017/S0007114523001770 -
Molecular and Cellular Biochemistry Aug 2023Non-alcoholic fatty liver (NAFLD) is a widespread disease with various complications including Non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis and...
Non-alcoholic fatty liver (NAFLD) is a widespread disease with various complications including Non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis and ultimately hepatocellular carcinoma (HCC). Up till now there is no FDA approved drug for treatment of NAFLD. Flavonoids such as Rhamnetin (Rhm) have been ascribed effective anti-inflammatory and anti-oxidative properties. Thus, Rhm as a potent flavonoid could target multiple pathological cascades causing NAFLD to prevent its progression into HCC. NAFLD is a multifactorial disease and its pathophysiology is complex and is currently challenged by the 'Multiple-hit hypothesis' that includes wider range of comorbidities rather than previously established theory of 'Two-hit hypothesis'. Herein, we aimed at establishing reliable in vitro NASH models using different mixtures of variable ratios and concentrations of oleic acid (OA) and palmitic acid (PA) combinations using HepG2 cell lines. Moreover, we compared those models in the context of oil red staining, triglyceride levels and their altered downstream molecular signatures for genes involved in de novo lipogenesis, inflammation, oxidative stress and apoptotic machineries as well. Lastly, the effect of Rhm on NASH and HCC models was deeply investigated. Over the 10 NASH models tested, PA 500 µM concentration was the best model to mimic the molecular events of steatosis induced NAFLD. Rhm successfully ameliorated the dysregulated molecular events caused by the PA-induced NASH. Additionally, Rhm regulated inflammatory and oxidative machinery in the HepG2 cancerous cell lines. In conclusion, PA 500 µM concentration is considered an effective in vitro model to mimic NASH. Rhm could be used as a promising therapeutic modality against both NASH and HCC pathogenesis.
Topics: Humans; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Liver Neoplasms; Quercetin; Palmitic Acid; Flavonoids
PubMed: 36495373
DOI: 10.1007/s11010-022-04619-6 -
Military Medicine May 2024Acute respiratory distress syndrome (ARDS) is a widespread and often fatal clinical syndrome marked by the acute onset of pulmonary edema and inflammatory-mediated...
INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a widespread and often fatal clinical syndrome marked by the acute onset of pulmonary edema and inflammatory-mediated disruptions in alveolar-capillary permeability resulting in impaired gas exchange and tissue oxygenation with subsequent acute respiratory failure that accounts for 10.4% of all intensive care unit admissions worldwide and boasts a mortality rate of 38.5%. The current treatment for ARDS remains largely supportive. This is largely because of the many challenges of achieving a stable and sustainable animal model that recreates the pathophysiology of ARDS experimentally in a controlled setting to allow research to elucidate potential treatments of ARDS moving forward.
MATERIALS AND METHODS
The bronchoalveolar lavage and oleic acid models are currently the 2 most frequently used experimental models in inducing ARDS in animal models. This study demonstrated that combining them into a "two-hit model" can produce sustained ARDS in swine models per the Horowitz index (PaO2/FiO2 ratio of ≤300 mmHg). Additionally, expected changes in pH, pCO2, lung compliance, cytokines, and tissue histopathology were observed and add to our confidence and reliability that the "two-hit model" produces symptomatic ARDS in a manner very similar to that observed in humans.
RESULTS AND CONCLUSIONS
In conclusion, we demonstrated a viable animal model of human ARDS that is maintained for a prolonged period, suitable for continuous monitoring of the progression, and evaluation of potential future treatments and procedures to reduce patient morbidity and mortality. To carry out this two-hit model, lung injury was induced through a combination of bronchoalveolar lavage and oleic acid administration and the disease process of ARDS is subsequently tracked through clinically relevant parameters such as respiratory mechanics, cytokine response, aretrial blood gas (ABG) changes, and observation of postmortem histopathologic changes. This promising new model has the capacity to successfully replicate human ARDS which is a well-known and notoriously multifactorial pathogenic process to reproduce experimentally for an extended period of time. The "two-hit model" is a viable and appropriate model for the research of novel treatments for ARDS.
PubMed: 38771004
DOI: 10.1093/milmed/usae191 -
ACS Applied Bio Materials Apr 2024Deformable nanovesicles have a crucial role in topical drug delivery through the skin, due to their capability to pass intact the stratum corneum and epidermis (SCE) and... (Review)
Review
Deformable nanovesicles have a crucial role in topical drug delivery through the skin, due to their capability to pass intact the stratum corneum and epidermis (SCE) and significantly increase the efficacy and accumulation of payloads in the deeper layers of the skin. Namely, lipid-based ultradeformable nanovesicles are versatile and load bioactive molecules with different physicochemical properties. For this reason, this study aims to make oleic acid based nanovesicles (oleosomes) for the codelivery of icariin and sodium naproxen and increase their permeation through the skin. Oleosomes have suitable physicochemical properties and long-term stability for a potential dermal or transdermal application. The inclusion of oleic acid in the lipid bilayer increases 3-fold the deformable properties of oleosomes compared to conventional liposomes and significantly improves the percutaneous permeation of icariin and sodium naproxen through the human SCE membranes compared to hydroalcoholic solutions of both drugs. The tolerability studies on human volunteers demonstrate that oleosomes are safer and speed up the recovery of transepidermal water loss (TEWL) baselines compared to saline solution. These results highlight promising properties of icariin/sodium naproxen coloaded oleosomes for the treatment of skin disorders and suggest the potential future applications of these nanovesicles for further experiments.
PubMed: 38608313
DOI: 10.1021/acsabm.4c00067 -
Scientific Reports Jan 2024Skeletal muscle is one of the largest metabolic tissues in mammals and is composed of four different types of muscle fibers (types 1, 2A, 2X, and 2B); however, type 2B...
Skeletal muscle is one of the largest metabolic tissues in mammals and is composed of four different types of muscle fibers (types 1, 2A, 2X, and 2B); however, type 2B is absent in humans. Given that slow-twitch fibers are superior to fast-twitch fibers in terms of oxidative metabolism and are rich in mitochondria, shift of muscle fiber types in direction towards slower fiber types improves metabolic disorders and endurance capacity. We previously had reported that oleic acid supplementation increases type 1 fiber formation in C2C12 myotubes; however, its function still remains unclear. This study aimed to determine the effect of oleic acid on the muscle fiber types and endurance capacity. An in vivo mouse model was used, and mice were fed a 10% oleic acid diet for 4 weeks. Two different skeletal muscles, slow soleus muscle with the predominance of slow-twitch fibers and fast extensor digitorum longus (EDL) muscle with the predominance of fast-twitch fibers, were used. We found that dietary oleic acid intake improved running endurance and altered fiber type composition of muscles, the proportion of type 1 and 2X fibers increased in the soleus muscle and type 2X increased in the EDL muscle. The fiber type shift in the EDL muscle was accompanied by an increased muscle TAG content. In addition, blood triacylglycerol (TAG) and non-esterified fatty acid levels decreased during exercise. These changes suggested that lipid utilization as an energy substrate was enhanced by oleic acid. Increased proliferator-activated receptor γ coactivator-1β protein levels were observed in the EDL muscle, which potentially enhanced the fiber type transitions towards type 2X and muscle TAG content. In conclusion, dietary oleic acid intake improved running endurance with the changes of muscle fiber type shares in mice. This study elucidated a novel functionality of oleic acid in skeletal muscle fiber types. Further studies are required to elucidate the underlying mechanisms. Our findings have the potential to contribute to the field of health and sports science through nutritional approaches, such as the development of supplements aimed at improving muscle function.
Topics: Humans; Animals; Mice; Oleic Acid; Muscle Fibers, Skeletal; Muscle, Skeletal; Cell Respiration; Dietary Supplements; Mammals
PubMed: 38191891
DOI: 10.1038/s41598-023-50464-y -
Domestic Animal Endocrinology Jul 2024Insulin is a potent adipogenic hormone that triggers a series of transcription factors that regulate the differentiation of preadipocytes into mature adipocytes.... (Review)
Review
Insulin is a potent adipogenic hormone that triggers a series of transcription factors that regulate the differentiation of preadipocytes into mature adipocytes. Ciglitazone specifically binds to peroxisome proliferator-activated receptor-γ (PPARγ), thereby promoting adipocyte differentiation. As a natural ligand of PPARγ, oleic acid (OA) can promote the translocation of PPARγ into the nucleus, regulate the expression of downstream genes, and promote adipocyte differentiation. We hypothesized that ciglitazone and oleic acid interact with insulin to enhance bovine preadipocyte differentiation. Preadipocytes were cultured 96 h in differentiation medium containing 10 mg/L insulin (I), 10 mg/L insulin + 10 µM cycloglitazone (IC), 10 mg/L insulin + 100 µM oleic acid (IO), or 10 mg/L insulin + 10 µM cycloglitazone+100 µM oleic acid (ICO). Control preadipocytes (CON) were cultured in differentiation medium (containing 5% fetal calf serum). The effects on the differentiation of Yanbian cattle preadipocytes were examined using molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. I, IC, IO, and ICO treatments produced higher concentrations of triglycerides (TAG) and lipid droplet accumulation in preadipocytes compared with CON treatment (P < 0.05). Co-treatment of insulin and PPARγ agonists significantly increased the expression of genes involved in regulating adipogenesis and fatty acid synthesis. (P < 0.05). Differential expression analysis identified 1488, 1764, 1974 and 1368 DEGs in the I, IC, IO and ICO groups, respectively. KEGG pathway analysis revealed DEGs mainly enriched in PPAR signalling, FOXO signaling pathway and fatty acid metabolism. These results indicate that OA, as PPARγ agonist, can more effectively promote the expression of bovine lipogenesis genes and the content of TAG and adiponectin when working together with insulin, and stimulate the differentiation of bovine preadipocytes. These findings provide a basis for further screening of relevant genes and transcription factors in intramuscular fat deposition and meat quality to enhance breeding programs.
Topics: Animals; Cattle; Adipocytes; PPAR gamma; Insulin; Cell Differentiation; Thiazolidinediones; Oleic Acid; Adipogenesis; Cells, Cultured; Gene Expression Regulation
PubMed: 38574690
DOI: 10.1016/j.domaniend.2024.106848