-
Biomedicine & Pharmacotherapy =... Jun 2024Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of... (Review)
Review
Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia.
PubMed: 38908209
DOI: 10.1016/j.biopha.2024.116917 -
Biomedicine & Pharmacotherapy =... Jun 2024Obesity aggravates ferroptosis, and vitamin D (VD) may inhibit ferroptosis. We hypothesized that weight reduction and/or calcitriol administration have benefits against...
Obesity aggravates ferroptosis, and vitamin D (VD) may inhibit ferroptosis. We hypothesized that weight reduction and/or calcitriol administration have benefits against the sepsis-induced liver redox imbalance and ferroptosis in obese mice. Mice were fed a high-fat diet for 11 weeks, then half of the mice continued to consume the diet, while the other half were transferred to a low-energy diet for 5 weeks. After feeding the respective diets for 16 weeks, sepsis was induced by cecal ligation and puncture (CLP). Septic mice were divided into four experimental groups: OS group, obese mice injected with saline; OD group, obese mice with calcitriol; WS group, weight-reduction mice with saline; and WD group, weight-reduction mice with calcitriol. Mice in the respective groups were euthanized at 12 or 24 h after CLP. Results showed that the OS group had the highest inflammatory mediators and lipid peroxide levels in the liver. Calcitriol treatment reduced iron content, enhanced the reduced glutathione/oxidized glutathione ratio, upregulated nuclear factor erythroid 2-related factor 2, ferroptosis-suppressing protein 1, and solute carrier family 7 member 11 expression levels. Also, mitochondrion-associated nicotinamide adenine dinucleotide phosphate oxidase 1, peroxisome proliferator-activated receptor-γ coactivator 1, hypoxia-inducible factor-1α, and heme oxidase-1 expression levels increased in the late phase of sepsis. These results were not noted in the WS group. These findings suggest that calcitriol treatment elicits a more-balanced glutathione redox status, alleviates liver ferroptosis, and enhances mitochondrial biogenesis-associated gene expressions. Weight reduction alone had minimal influences on liver ferroptosis and mitochondrial biogenesis in obese mice with sepsis.
PubMed: 38906016
DOI: 10.1016/j.biopha.2024.116926 -
Frontiers in Toxicology 2024Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and...
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (, , , -) and downregulation of lipid transport genes (, , ). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis () and bile acid synthesis () were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis () showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.
PubMed: 38903859
DOI: 10.3389/ftox.2024.1390196 -
Cardiovascular Diabetology Jun 2024Recently deorphanized G protein-coupled receptor 146 (GPR146) was shown to respond to signal from a newly identified hormone-cholesin-and to play a role in hepatic lipid...
BACKGROUND
Recently deorphanized G protein-coupled receptor 146 (GPR146) was shown to respond to signal from a newly identified hormone-cholesin-and to play a role in hepatic lipid metabolism. However, the importance of its biological activity in human organism remains elusive, mainly due to the lack of studies on human tissues up to this point. This study aimed to identify the cholesin receptor-associated genes and clinical factors linked with their expression in cardiovascular system and associated adipose tissues.
METHODS
Right cardiac auricle, aortic wall, saphenous vein, and adipose tissue (periaortic-PAT, epicardial-EAT, thymic-TAT) samples were collected during coronary artery bypass grafting. Clinical records of the study participants were assessed for the presence of diabetes, medications taken and serum cholesterol levels. GPR146 mRNA expression in all gathered tissues was assessed with qPCR, and RNA seqencing was performed in selected tissues of 20 individuals to identify pathways associated with GPR146 expression.
RESULTS
We included 46 participants [37 male, 23 with type 2 diabetes, median age 68.50 (Q1-Q3: 63.00-72.00) years, BMI 28.39 (26.06-31.49) kg/m]. GPR146 expression in adipose tissues significantly correlated with BMI, c-peptide, total cholesterol, and LDL concentrations. Selected metabolic pathways were significantly and positively enriched in GPR146-dependent manner. GPR146-coexpressed genes contained key regulators of lipid metabolism involved in such pathways as fatty acid metabolism, tricarboxilic acid cycle and peroxisomal metabolism. Those genes correlated positively with serum concentrations of LDL, HDL, and total cholesterol. SGLT2i treatment was associated with inversion of GPR146-related signature in EAT, suggesting potential impact on cholesin-GPR146 network.
CONCLUSIONS
GPR146 expression is associated with serum lipids and metabolically-relevant transcriptomic changes in EAT similar to SGLT2i-associated ones.
Topics: Humans; Male; Middle Aged; Female; Aged; Receptors, G-Protein-Coupled; Sodium-Glucose Transporter 2 Inhibitors; Signal Transduction; Diabetes Mellitus, Type 2; Adipose Tissue; Treatment Outcome; Biomarkers
PubMed: 38902687
DOI: 10.1186/s12933-024-02322-y -
Neural Regeneration Research Jun 2024The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration. Axons and dendrites, sometimes referred to as neurites, are...
The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration. Axons and dendrites, sometimes referred to as neurites, are extensions of a neuron's cellular body that are used to start networks. Here we explored the effects of diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate (DDQ) on neurite developmental features in HT22 neuronal cells. In this work, we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22 cells expressing mutant Tau (mTau) cDNA. To investigate DDQ characteristics, cell viability, biochemical, molecular, western blotting, and immunocytochemistry were used. Neurite outgrowth is evaluated through the segmentation and measurement of neural processes. These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth. These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22. DDQ-treated mTau-HT22 cells (HT22 cells transfected with cDNA mutant Tau) were seen to display increased levels of synaptophysin, MAP-2, and β-tubulin. Additionally, we confirmed and noted reduced levels of both total and p-Tau, as well as elevated levels of microtubule-associated protein 2, β-tubulin, synaptophysin, vesicular acetylcholine transporter, and the mitochondrial biogenesis protein-peroxisome proliferator-activated receptor-gamma coactivator-1α. In mTau-expressed HT22 neurons, we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth. Our findings conclude that mTau-HT22 (Alzheimer's disease) cells treated with DDQ have functional neurite developmental characteristics. The key finding is that, in mTau-HT22 cells, DDQ preserves neuronal structure and may even enhance nerve development function with mTau inhibition.
PubMed: 38902281
DOI: 10.4103/NRR.NRR-D-24-00157 -
Cell Reports Jun 2024Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues...
Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.
PubMed: 38900635
DOI: 10.1016/j.celrep.2024.114364 -
PPAR Research 2024We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator-activated receptor- (), referred to as . This variant,...
We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator-activated receptor- (), referred to as . This variant, encoding the PPAR1 protein, is abundantly and ubiquitously expressed, playing a crucial role in adipogenesis. possesses a unique promoter and 5' untranslated region (5'UTR), distinct from those of the canonical mouse and mRNAs. We observed a significant increase in DNA methylation at two CpG sites within the proximal promoter region (-733 to -76) of during adipocyte differentiation. Concurrently, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) using antibodies against H3K4me3 and H3K27ac indicated marked elevations in both methylation and acetylation of histone H3, while the repressive histone mark H3K9me2 significantly decreased, at the transcription start sites of both and following differentiation. Knocking down using specific siRNA also led to a decrease in mRNA and PPAR2 protein levels; conversely, knocking down resulted in reduced mRNA and PPAR1 protein levels, suggesting synergistic transcriptional regulation of and during adipogenesis. Furthermore, our experiments utilizing the CRISPR-Cas9 system identified crucial PPAR-binding sites within the gene locus, underscoring their significance in adipogenesis. Based on these findings, we propose a model of positive feedback regulation for and expression during the adipocyte differentiation process in 3T3-L1 cells.
PubMed: 38899160
DOI: 10.1155/2024/5518933 -
Physiological Reports Jun 2024This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O [10 min] and 30% O [15 min]) affects exercise performance in mice. Three...
This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O [10 min] and 30% O [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor-A (BF ≥10), PPAR-α (BF ≥3), and PPAR-γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise-trained (ET) group. INT group exhibited significantly higher activity levels of 3-hydroxyacyl-CoA-dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT-PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.
Topics: Animals; Male; Muscle, Skeletal; Mice; Physical Conditioning, Animal; Physical Endurance; Mice, Inbred C57BL; Hyperoxia; PPAR alpha; PPAR gamma; Phosphofructokinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors; DNA-Binding Proteins; Mitochondrial Proteins
PubMed: 38898524
DOI: 10.14814/phy2.16117 -
BioRxiv : the Preprint Server For... Jun 2024Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase...
Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
PubMed: 38895318
DOI: 10.1101/2024.06.03.597253 -
Nutrients May 2024This study examined whey protein's impact on insulin resistance in a high-fat diet-induced pediatric obesity mouse model. Pregnant mice were fed high-fat diets, and male...
This study examined whey protein's impact on insulin resistance in a high-fat diet-induced pediatric obesity mouse model. Pregnant mice were fed high-fat diets, and male pups continued this diet until 8 weeks old, then were split into high-fat, whey, and casein diet groups. At 12 weeks old, their body weight, fasting blood glucose (FBG), blood insulin level (IRI), homeostatic model assessment for insulin resistance (HOMA-IR), liver lipid metabolism gene expression, and liver metabolites were compared. The whey group showed significantly lower body weight than the casein group at 12 weeks old ( = 0.034). FBG was lower in the whey group compared to the high-fat diet group ( < 0.01) and casein group ( = 0.058); IRI and HOMA-IR were reduced in the whey group compared to the casein group ( = 0.02, < 0.01, < 0.01, respectively). The levels of peroxisome proliferator-activated receptor α and hormone-sensitive lipase were upregulated in the whey group compared to the casein group ( < 0.01, = 0.03). Metabolomic analysis revealed that the levels of taurine and glycine, both known for their anti-inflammatory and antioxidant properties, were upregulated in the whey group in the liver tissue ( < 0.01, < 0.01). The intake of whey protein was found to improve insulin resistance in a high-fat diet-induced pediatric obesity mouse model.
Topics: Animals; Whey Proteins; Insulin Resistance; Diet, High-Fat; Male; Mice; Disease Models, Animal; Pediatric Obesity; Liver; Female; Blood Glucose; Insulin; Lipid Metabolism; Pregnancy; Mice, Inbred C57BL
PubMed: 38892554
DOI: 10.3390/nu16111622