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Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.PloS One 2024Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive...
AIM
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH.
METHODS
Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.
RESULTS
CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.
CONCLUSION
S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
Topics: Animals; Sphingosine; Lysophospholipids; Liver Cirrhosis; Mice; Hepatic Stellate Cells; Phosphotransferases (Alcohol Group Acceptor); Humans; Sphingosine-1-Phosphate Receptors; Fatty Liver; Male; Mice, Knockout; Mice, Inbred C57BL; Liver; Choline Deficiency; Endothelial Cells; Receptors, Lysosphingolipid; Pyrazoles; Pyridines
PubMed: 38753743
DOI: 10.1371/journal.pone.0303296 -
Maedica Mar 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is an entity with a growing incidence but only a few pharmacological options. In Romania, the prevalence...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an entity with a growing incidence but only a few pharmacological options. In Romania, the prevalence of MASLD has been increasing, while that of viral hepatitis has been decreasing. The purpose of this study is to compare two supplements for the treatment of MASLD. Between January 2020 and May 2022, 90 patients with MASLD were randomized to receive either silymarin 150 mg b.i.d (45 subjects) or essential phospholipids (EPLs) 825 mg b.i.d. (45 subjects) for six months. All study participants received recommendations for lifestyle and diet modifications. Assessment of the severity of steatosis and liver fibrosis was performed using FibroScan® with controlled attenuated parameter (CAP) at the beginning and end of treatment. A total of 68 patients completed the trial. The two groups were statistically comparable in terms of clinical, biological and FibroScanR parameters. Aspartate transferase (AST) decreased from a median of 40 to 28 IU/L in the EPL arm (compared to 25→¨25.5 IU/L in the silymarin arm) (p-value=0.11) and alanine transaminase (ALT) decreased from 46 to 37.5 IU/L (compared to 31→30 IU/L) (p-value = 0.38). Plasma cholesterol levels also decreased significantly in the EPL group (218→189.5 mg/dL) compared to the silymarin arm (217→209 mg/dL) (p = 0.01). At the end of treatment, liver stiffness decreased by 0.7 KPa (6.9→6.2 KPa) in the EPL group but increased by 2.3 KPa (7.2→9.5 KPa) in the silymarin group (p = 0.1). The reduction in hepatic steatosis was comparable between the two groups: it decreased by 5% of the initial value. In our study, a six-month treatment with EPLs was superior to silymarin in MASLD patients because it succeeded in improving both laboratory parameters and liver fibrosis, as estimated by FibroScan®.
PubMed: 38736928
DOI: 10.26574/maedica.2024.19.11.9 -
Nutrients Apr 2024Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid...
Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid markers for RCC remain unidentified. We aimed to discover and validate potent plasma markers and their association with dietary fats. Using lipid metabolite quantification, machine-learning algorithms, and marker validation, we identified RCC diagnostic markers in studies involving 60 RCC and 167 healthy controls (HC), as well as 27 RCC and 74 HC, by analyzing their correlation with dietary fats. RCC was associated with altered metabolism in amino acids, glycerophospholipids, and glutathione. We validated seven markers (l-tryptophan, various lysophosphatidylcholines [LysoPCs], decanoylcarnitine, and l-glutamic acid), achieving a 96.9% AUC, effectively distinguishing RCC from HC. Decreased decanoylcarnitine, due to reduced carnitine palmitoyltransferase 1 (CPT1) activity, was identified as affecting RCC risk. High intake of polyunsaturated fatty acids (PUFAs) was negatively correlated with LysoPC (18:1) and LysoPC (18:2), influencing RCC risk. We validated seven potential markers for RCC diagnosis, highlighting the influence of high PUFA intake on LysoPC levels and its impact on RCC occurrence via CPT1 downregulation. These insights support the efficient and accurate diagnosis of RCC, thereby facilitating risk mitigation and improving patient outcomes.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Case-Control Studies; Male; Female; Middle Aged; Biomarkers, Tumor; Aged; Fatty Acids, Unsaturated; Carnitine O-Palmitoyltransferase; Adult; Lysophosphatidylcholines; Carnitine; Machine Learning; Lipid Metabolism; Tryptophan
PubMed: 38732512
DOI: 10.3390/nu16091265 -
International Journal of Molecular... Apr 2024The plant-derived α-linolenic acid (ALA) is an essential n-3 acid highly susceptible to oxidation, present in oils of flaxseeds, walnuts, canola, perilla, soy, and... (Review)
Review
The plant-derived α-linolenic acid (ALA) is an essential n-3 acid highly susceptible to oxidation, present in oils of flaxseeds, walnuts, canola, perilla, soy, and chia. After ingestion, it can be incorporated in to body lipid pools (particularly triglycerides and phospholipid membranes), and then endogenously metabolized through desaturation, elongation, and peroxisome oxidation to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with a very limited efficiency (particularly for DHA), beta-oxidized as an energy source, or directly metabolized to C18-oxilipins. At this moment, data in the literature about the effects of ALA supplementation on metabolic syndrome (MetS) in humans are inconsistent, indicating no effects or some positive effects on all MetS components (abdominal obesity, dyslipidemia, impaired insulin sensitivity and glucoregulation, blood pressure, and liver steatosis). The major effects of ALA on MetS seem to be through its conversion to more potent EPA and DHA, the impact on the n-3/n-6 ratio, and the consecutive effects on the formation of oxylipins and endocannabinoids, inflammation, insulin sensitivity, and insulin secretion, as well as adipocyte and hepatocytes function. It is important to distinguish the direct effects of ALA from the effects of EPA and DHA metabolites. This review summarizes the most recent findings on this topic and discusses the possible mechanisms.
Topics: Metabolic Syndrome; Humans; alpha-Linolenic Acid; Animals; Fatty Acids, Unsaturated; Dietary Supplements; Insulin Resistance
PubMed: 38732139
DOI: 10.3390/ijms25094909 -
Scientific Reports May 2024This study was conducted to verify the essentiality of dietary cholesterol for early juvenile slipper lobster, Thenus australiensis (initial weight 4.50 ± 0.72 g,...
This study was conducted to verify the essentiality of dietary cholesterol for early juvenile slipper lobster, Thenus australiensis (initial weight 4.50 ± 0.72 g, mean ± SD, CV = 0.16), and to explore the potential for interactions between dietary cholesterol and phospholipid. An 8-week experiment was conducted using six experimental feeds containing three supplemental cholesterol concentrations (0, 0.2 and 0.4% dry matter) at two supplemental phospholipid concentrations (0% and 1.0% dry matter). Dietary cholesterol concentrations of ≥ 0.2% resulted in up to threefold greater weight gain compared to 0% dietary cholesterol, but without any significant main or interactive dietary phospholipid effect. An interaction was observed for lobster survival with lowest survival (46%) recorded for combined 0% cholesterol and 0% phospholipid compared to every other treatment (71-100%). However, all surviving lobsters at 0% dietary cholesterol, regardless of dietary phospholipid level, were in poor nutritional condition. Apparent feed intake (AFI) was significantly higher at dietary cholesterol ≥ 0.2% but was lower for each corresponding dietary cholesterol level at 1% dietary phospholipid. This implied that the feed conversion ratio was improved with supplemental phospholipid. In conclusion, this study confirms the essential nature of dietary cholesterol and that dietary phospholipid can provide additional benefits.
Topics: Animals; Phospholipids; Cholesterol, Dietary; Palinuridae; Animal Feed; Animal Nutritional Physiological Phenomena
PubMed: 38710742
DOI: 10.1038/s41598-024-60367-1 -
Journal of Fish Biology May 2024Estuaries are considered as key habitats for the early life stages of fish. However, in the face of massive destruction of many estuarine intertidal areas, management...
Lipids as biomarkers to assess the nutritional and physiological status of two diadromous fish (Anguilla anguilla and Chelon auratus) at early life stages in a temperate macrotidal estuary.
Estuaries are considered as key habitats for the early life stages of fish. However, in the face of massive destruction of many estuarine intertidal areas, management and conservation measures are needed. Fish condition indicators may be used as a proxy of habitat quality and provide valuable information for management of coastal areas. In this study, the larvae of golden mullet (Chelon auratus) and European glass eels (Anguilla anguilla) were sampled in three sites of the Gironde Estuary. Different lipid classes and fatty acids were quantified: phospholipids (globally, phosphatidylethanolamine and phosphatidylcholine), triglycerides, omega-3 (particularly docosahexaenoic and eicosapentaenoic acids), omega-6 and C18:1. These biomarkers provide information on the nutritional status of the larvae as well as on prey availability and larvae diet between sites. One site significantly differed from the others as it seemed to offer abundant and better-quality prey. The very high levels of omega-3 contained in mullet larvae suggested that this site provided a high amount of diatoms. However, the mullet larvae that colonized this site also showed physiological stress that could be explained by exposure to pollutants through their prey. This work constitutes an essential baseline for developing biomarkers to assess the quality of habitats in a global change context.
PubMed: 38706152
DOI: 10.1111/jfb.15762 -
Journal of Oleo Science 2024This study was to investigate the effects of Smilax China L. saponins (SCS) on non-alcoholic fatty liver disease (NAFLD). Rats were fed a high-fat diet (HFD) for 8 weeks...
This study was to investigate the effects of Smilax China L. saponins (SCS) on non-alcoholic fatty liver disease (NAFLD). Rats were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by SCS treatment for 8 weeks. The effect of SCS on liver injury was observed by H&E staining and the regulative mechanism of SCS on lipid formation was exposed by detecting Oil red O, insulin resistance (IR), and fatty acids synthesis (FAS). Furthermore, transcriptomics and metabolomics were performed to analyze the potential targets. The experimental results indicated that SCS exerted a positive curative effect in alleviating HFD-induced overweight, hepatic injury, steatosis, and lipid formation and accumulation in rats, and the preliminary mechanism studies showed that SCS could alleviate IR, inhibit FAS expression, and reduce Acetyl-CoA levels. Besides, the integrative analysis of transcriptomics and metabolomics exposed the targets of SCS to regulate lipid production likely being the sphingolipid metabolism and glycerophospholipid metabolism pathways. This study demonstrates that SCS significantly ameliorates lipid metabolic disturbance in rats with NAFLD by relieving insulin resistance, inhibiting the FAS enzymes, and regulating the sphingolipid and glycerophospholipid metabolism pathways.
Topics: Animals; Smilax; Saponins; Non-alcoholic Fatty Liver Disease; Male; Insulin Resistance; Metabolomics; Diet, High-Fat; Transcriptome; Lipid Metabolism; Rats; Rats, Sprague-Dawley; Sphingolipids; Glycerophospholipids; Liver; Disease Models, Animal
PubMed: 38692892
DOI: 10.5650/jos.ess23167 -
Frontiers in Bioscience (Landmark... Apr 2024The effect of the daily consumption of a low-fat yogurt (150 g) enriched with Platelet-Activating Factor receptor (PAF-R) antagonists, or the plain one, on gut... (Randomized Controlled Trial)
Randomized Controlled Trial
Does Yogurt Enriched with Platelet-Activating Factor Inhibitors from Olive Oil By-Products Affect Gut Microbiota and Faecal Metabolites in Healthy Overweight Subjects? (A randomized, parallel, three arm trial.).
OBJECTIVE
The effect of the daily consumption of a low-fat yogurt (150 g) enriched with Platelet-Activating Factor receptor (PAF-R) antagonists, or the plain one, on gut microbiota and faecal metabolites was investigated in healthy overweight subjects.
METHODS
A randomized, three-arm, double-blind, placebo-controlled, parallel-group study was performed that lasted 8 weeks. Blood and stools were collected and analyzed before and after the intervention.
RESULTS
Our findings revealed that the intake of the enriched yogurt resulted in a significant increase in the levels of spp., group and Firmicutes-to-Bacteroidetes (F/B) ratio. On the other hand, a significant increase in the levels of and group was detected after the intake of the plain yogurt. The increase in the levels of group was inversely associated with the plasma catabolic enzyme of PAF, namely LpPLA2 (lipoprotein-associated phospholipase A2), a cardiovascular risk marker that has been linked with inflammation and atherosclerosis. Moreover, in the enriched with PAF-R antagonists yogurt group, the increased levels of group were also associated with lower PAF action assessed as human platelet-rich plasma (PRP) aggregation. Additionally, a higher % increase in molar ratio of Branched Short Chain Fatty Acids (BSCFAs) was detected for both yogurt groups after the 8 week-intervention compared to control. The consumption of the enriched yogurt also resulted in a significant drop in faecal caproic levels and a trend for lower ratio of butyrate to total volatile fatty acids (VFAs) compared to baseline levels.
CONCLUSION
Yogurt consumption seems to favorably affect gut microbiota while its enrichment with PAF-R antagonists from olive oil by-products, may provide further benefits in healthy overweight subjects.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov (NCT02259205).
Topics: Humans; Yogurt; Gastrointestinal Microbiome; Overweight; Olive Oil; Feces; Male; Female; Adult; Double-Blind Method; Middle Aged; Platelet Activating Factor; Receptors, G-Protein-Coupled; Platelet Membrane Glycoproteins
PubMed: 38682205
DOI: 10.31083/j.fbl2904159 -
Journal of the American Society For... Jun 2024Bone fracture healing is a complex process in which specific molecular knowledge is still lacking. The citrulline-arginine-nitric oxide metabolism is one of the involved...
Bone fracture healing is a complex process in which specific molecular knowledge is still lacking. The citrulline-arginine-nitric oxide metabolism is one of the involved pathways, and its enrichment via citrulline supplementation can enhance fracture healing. This study investigated the molecular effects of citrulline supplementation during the different fracture healing phases in a rat model. Microcomputed tomography (μCT) was applied for the analysis of the fracture callus formation. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and liquid-chromatography tandem mass spectrometry (LC-MS/MS) were used for lipid and protein analyses, respectively. μCT analysis showed no significant differences in the fracture callus volume and volume fraction between the citrulline supplementation and control group. The observed lipid profiles for the citrulline supplementation and control group were distinct for the different fracture healing stages. The main contributing lipid classes were phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs). The changing effect of citrulline supplementation throughout fracture healing was indicated by changes in the differentially expressed proteins between the groups. Pathway analysis showed an enhancement of fracture healing in the citrulline supplementation group in comparison to the control group via improved angiogenesis and earlier formation of the soft and hard callus. This study showed the molecular effects on lipids, proteins, and pathways associated with citrulline supplementation during bone fracture healing, even though no effect was visible with μCT.
Topics: Animals; Fracture Healing; Rats; Citrulline; Rats, Sprague-Dawley; Tandem Mass Spectrometry; X-Ray Microtomography; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Dietary Supplements; Disease Models, Animal; Male; Bony Callus; Chromatography, Liquid; Lysophosphatidylcholines; Phosphatidylcholines
PubMed: 38679918
DOI: 10.1021/jasms.4c00028 -
Journal of Ethnopharmacology Sep 2024Plantaginis Semen (PS) is widely utilized as a common herb in several Asian countries, particularly China, due to its diuretic, anti-hypertensive, anti-hyperlipidemic,...
ETHNOPHARMACOLOGICAL RELEVANCE
Plantaginis Semen (PS) is widely utilized as a common herb in several Asian countries, particularly China, due to its diuretic, anti-hypertensive, anti-hyperlipidemic, and anti-hyperglycemic properties. Furthermore, it is acknowledged for its ability to mitigate renal complications associated with metabolic syndrome. Despite its extensive usage, there is limited systematic literature elucidating its therapeutic mechanisms, thus emphasizing the necessity for comprehensive investigations in this field.
AIM
This study aims to comprehensively evaluate the therapeutical potential of PS in treating diabetic kidney disease (DKD) and to elucidate the underlying mechanisms through in vivo and in vitro models.
METHODS
The main composition of PS were characterized using the UPLC-QTOF-MS method. For the in vivo investigation, a mouse model mediated by streptozocin (STZ) associated with a high-fat diet (HFD) and unilateral renal excision was established. The mice were split into 6 groups (n = 8): control group (CON group), DKD group, low-dose of Plantago asiatica L. seed extract group (PASE-L group, 3 g/kg/d), medium-dose of PASE group (PASE-M, 6 g/kg/d), high-dose of PASE group (PASE-H, 9 g/kg/d), and positive drug group (valsartan, VAS group, 12 mg/kg/d). After 8 weeks of treatment, the damage induced by DKD was evaluated by using relevant parameters of urine and blood. Furthermore, indicators of inflammation and factors associated with the SphK1-S1P signaling pathway were investigated. For the in vitro study, the cell line HBZY-1 was stimulated by high glucose (HG), they were then co-cultured with different concentrations of PASE, and the corresponding associated inflammatory and sphingosine kinase 1/sphingosine-1-phosphate (SphK1-S1P) factors were examined.
RESULTS
A total of 59 major components in PS were identified, including flavonoids, iridoids, phenylethanol glycosides, guanidine derivatives, and fatty acids. In the mouse model, PS was found to significantly improve body weight, decrease fasting blood glucose (FBG) levels, increased glucose tolerance and insulin tolerance, improved kidney-related markers compared to the DKD group, pathological changes in the kidneys also improved dramatically. These effects showed a dose-dependent relationship, with higher PASE concentrations yielding significantly better outcomes than lower concentrations. However, the effects of the low PASE concentration were not evident for some indicators. In the cellular model, the high dose of PASE suppressed high glucose (HG) stimulated renal mesangial cell proliferation, suppressed inflammatory factors and NF-κB, and decreased the levels of fibrillin-1(FN-1) and collagen IV(ColIV).
CONCLUSION
Our results indicate that PS exerts favorable therapeutic effects on DKD, with the possible mechanisms including the inhibition of inflammatory pathways, suppression of mRNA levels and protein expressions of SphK1 and S1P, consequently leading to reduced overexpression of FN-1 and ColIV, thereby warranting further exploration.
Topics: Animals; Diabetic Nephropathies; Male; Sphingosine; Lysophospholipids; Mice; Diabetes Mellitus, Experimental; Plant Extracts; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Kidney
PubMed: 38677576
DOI: 10.1016/j.jep.2024.118221