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1.
Mol Metab ; 81: 101887, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38280449

RESUMO

OBJECTIVE: Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. METHODS: Male and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10-12 and 16-18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. RESULTS: All groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. CONCLUSIONS: TAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Animais , Feminino , Masculino , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Secreção de Insulina , Rim/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Obesidade/metabolismo
2.
Obes Sci Pract ; 10(1): e716, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38263987

RESUMO

Introduction: Adipose triglyceride lipase (ATGL) is a crucial enzyme responsible for the release of fatty acids from various tissues. The expression of ATGL is regulated by insulin and this enzyme is linked to Insulin resistance (IR). On the other hand, ATGL-mediated lipolysis is connected to macrophage function and thus, ATGL is involved in inflammation and the pathogenesis of lipid-related disorders. This study aimed to investigate the correlation between ATGL, obesity, Metabolic Syndrome (MetS), and inflammation. Methods: A total of 100 participants, including 50 individuals with obesity and 50 healthy participants, were recruited for this study and underwent comprehensive clinical evaluations. Blood samples were collected to measure plasma lipid profiles, glycemic indices, and liver function tests. Additionally, peripheral blood mononuclear cells (PBMCs) were isolated and used for the assessment of the gene expression of ATGL, using real-time PCR. Furthermore, PBMCs were cultured and exposed to lipopolysaccharides (LPS) with simultaneous ATGL inhibition, and the gene expression of inflammatory cytokines, along with the secretion of prostaglandin E2 (PGE2), were measured. Results: The gene expression of ATGL was significantly elevated in PBMCs obtained from participants with obesity and was particularly higher in those diagnosed with MetS. It exhibited a correlation with insulin levels and Homeostatic Model Assessment for IR (HOMA-IR), and it was associated with lipid accumulation in the liver. Stimulation with LPS increased ATGL expression in PBMCs, while inhibition of ATGL attenuated the inflammatory responses induced by LPS. Conclusions: Obesity and MetS were associated with dysregulation of ATGL. ATGL might play a role in the upregulation of inflammatory cytokines and act as a significant contributor to the development of metabolic abnormalities related to obesity.

3.
J Mol Cell Biol ; 15(10)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37873692

RESUMO

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is one of the commonest causes of liver dysfunction. Adipose triglyceride lipase (ATGL) is closely related to lipid turnover and hepatic steatosis as the speed-limited triacylglycerol lipase in liver lipolysis. However, the expression and regulation of ATGL in NAFLD remain unclear. Herein, our results showed that ATGL protein levels were decreased in the liver tissues of high-fat diet (HFD)-fed mice, naturally obese mice, and cholangioma/hepatic carcinoma patients with hepatic steatosis, as well as in the oleic acid-induced hepatic steatosis cell model, while ATGL mRNA levels were not changed. ATGL protein was mainly degraded through the proteasome pathway in hepatocytes. Beta-transducin repeat containing (BTRC) was upregulated and negatively correlated with the decreased ATGL level in these hepatic steatosis models. Consequently, BTRC was identified as the E3 ligase for ATGL through predominant ubiquitination at the lysine 135 residue. Moreover, adenovirus-mediated knockdown of BTRC ameliorated steatosis in HFD-fed mouse livers and oleic acid-treated liver cells via upregulating the ATGL level. Taken together, BTRC plays a crucial role in hepatic steatosis as a new ATGL E3 ligase and may serve as a potential therapeutic target for treating NAFLD.


Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ácido Oleico/farmacologia , Ácido Oleico/metabolismo , Repetições WD40 , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL
4.
J Lipid Res ; 65(1): 100491, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38135254

RESUMO

Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be coactivated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein coactivation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for coactivation by CGI-58. ATGL variants with amino acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 coactivation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the coactivation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for coactivation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58-mediated coactivation of ATGL.


Assuntos
Inteligência Artificial , Lipase , Animais , Camundongos , Lipase/metabolismo , Lipólise/fisiologia , Triglicerídeos/metabolismo , Aminoácidos/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo
5.
J Lipid Res ; 64(12): 100462, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37871852

RESUMO

Genetic and biochemical evidence has established DDHD-domain containing 2 (DDHD2) as the principal triacylglycerol (TAG) hydrolase in neuronal lipolysis of cytosolic lipid droplets. In this issue of Journal of Lipid Research, Hofer et al. report that DDHD2 cooperates with adipose triglyceride lipase, the principal TAG hydrolase in adipose lipolysis, contributing to cytosolic hydrolysis of both TAG and diacylglycerols in murine neuroblastoma cells and primary cortical neurons via different configurations of the lipases. This finding highlights the complexity of cytosolic acylglycerol hydrolysis and raises many new questions in the field of lipid metabolism.


Assuntos
Glicerídeos , Lipólise , Animais , Camundongos , Lipólise/fisiologia , Triglicerídeos/metabolismo , Lipase/metabolismo , Neurônios/metabolismo
6.
Mol Metab ; 78: 101813, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37777008

RESUMO

OBJECTIVE: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain-SNS-adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. METHODS: We examined the role of lipolysis, and the brain-SNS-adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1ß (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with ß3 adrenergic agonist or undergoing restraint stress. RESULTS: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through ß3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. CONCLUSIONS: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.


Assuntos
Fígado Gorduroso Alcoólico , Fígado Gorduroso , Hepatopatias Alcoólicas , Ratos , Camundongos , Animais , Lipólise , Roedores/metabolismo , Fígado Gorduroso/patologia , Insulina/metabolismo , Etanol/efeitos adversos , Camundongos Knockout , Obesidade
7.
Mol Metab ; 76: 101791, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37586657

RESUMO

OBJECTIVES: Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids and precursors of oxygenated lipid mediators with diverse functions, including the control of cell growth, inflammation and tumourigenesis. However, the molecular pathways that control the availability of PUFAs for lipid mediator production are not well understood. Here, we investigated the crosstalk of three pathways in the provision of PUFAs for lipid mediator production: (i) secreted group X phospholipase A2 (GX sPLA2) and (ii) cytosolic group IVA PLA2 (cPLA2α), both mobilizing PUFAs from membrane phospholipids, and (iii) adipose triglyceride lipase (ATGL), which mediates the degradation of triacylglycerols (TAGs) stored in cytosolic lipid droplets (LDs). METHODS: We combined lipidomic and functional analyses in cancer cell line models to dissect the trafficking of PUFAs between membrane phospholipids and LDs and determine the role of these pathways in lipid mediator production, cancer cell proliferation and tumour growth in vivo. RESULTS: We demonstrate that lipid mediator production strongly depends on TAG turnover. GX sPLA2 directs ω-3 and ω-6 PUFAs from membrane phospholipids into TAG stores, whereas ATGL is required for their entry into lipid mediator biosynthetic pathways. ATGL controls the release of PUFAs from LD stores and their conversion into cyclooxygenase- and lipoxygenase-derived lipid mediators under conditions of nutrient sufficiency and during serum starvation. In starving cells, ATGL also promotes the incorporation of LD-derived PUFAs into phospholipids, representing substrates for cPLA2α. Furthermore, we demonstrate that the built-up of TAG stores by acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is required for the production of mitogenic lipid signals that promote cancer cell proliferation and tumour growth. CONCLUSION: This study shifts the paradigm of PLA2-driven lipid mediator signalling and identifies LDs as central lipid mediator production hubs. Targeting DGAT1-mediated LD biogenesis is a promising strategy to restrict lipid mediator production and tumour growth.


Assuntos
Gotículas Lipídicas , Neoplasias , Humanos , Gotículas Lipídicas/metabolismo , Fosfolipases A2 do Grupo X/metabolismo , Lipase/metabolismo , Ácidos Graxos Insaturados/metabolismo , Fosfolipídeos/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Neoplasias/metabolismo , Proliferação de Células
8.
J Anim Sci ; 1012023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37638641

RESUMO

Goat milk is enriched in fatty acids which are beneficial to human health. Previous research has revealed that 98% of milk fat is composed of triglycerides. However, the mechanisms regulating milk fat composition remain unclear. Forkhead box protein O1 (FoxO1) is a crucial regulatory factor involved in lipid metabolism across various cell types. Chromatin immunoprecipitation sequencing (ChIP)-seq data) and RNA sequencing (RNA-seq) data revealed that have indicated a close association between FoxO1 was closely related to lipid metabolism during lactation in dairy goats. The objective of this study was to investigate the mechanisms by which FoxO1 regulates lipid metabolism in goat mammary epithelial cells (GMECs). FoxO1 knockdown significantly downregulated the expression of adipose triglyceride lipase (ATGL) and suppressed the activity of the ATGL promoter. Consistently, the number of lipid droplets decreased significantly in FoxO1-overexpressing cells and increased in ATGL-knockdown cells. To further verify the effect of FoxO1 on ATGL promoter activity, cells were transfected with four promoter fragments of different lengths. We found that the core region of the ATGL promoter was located between -882 bp and -524 bp, encompassing two FoxO1 binding sites (FKH1 and FKH2). Mutations in the FoxO1 binding sites significantly downregulated ATGL promoter activity in GMECs. Luciferase reporter assays demonstrated that FoxO1 overexpression markedly enhanced ATGL promoter activity. Furthermore, site-directed mutation confirmed that FKH1 and FKH2 sites were simultaneously mutated significantly attenuated the stimulatory effect of FoxO1 on ATGL promoter activities simultaneous mutation of FKH1 and FKH2 sites significantly attenuated the stimulatory effect of FoxO1 on ATGL promoter activity. ChIP assays showed that FoxO1 directly binds to the FKH2 element located in the ATGL promoter in vivo. Finally, immunofluorescence staining revealed that insulin promotes the translocation of FoxO1 from the nucleus to the cytoplasm, thereby attenuating the FoxO1-induced activation of the ATGL promoter. Collectively, these findings uncover a novel pathway where by FoxO1 may regulate lipid metabolism in GMECs specifically by modulating the transcriptional activity of ATGL.


Forkhead box protein O1(FoxO1) is a key cellular regulatory factor that was involved in lipid metabolism in several cell types. This study was performed to explore the regulatory mechanism of FoxO1 in adipose triglyceride lipase (ATGL) promoter-driven transcription during lactation in dairy goats. Chromatin immunoprecipitation (ChIP)-seq and RNA sequencing (RNA-seq) data revealed that FoxO1 was closely related to lipid metabolism and inflammation during lactation in dairy goats. FoxO1 overexpression significantly decreased cellular triglyceride (TAG) content lipid droplet accumulation in goat mammary epithelial cells (GMECs), while ATGL knockdown attenuated this effect of FoxO1. Furthermore, the relative content of free fatty acid (FFAs) was markedly increased in FoxO1-overexpressed cells. Additionally, site-directed mutation and ChIP assays confirmed that FoxO1 promotes ATGL transcription through FoxO1 binding sites (FKH) located in the ATGL promoter. Moreover, insulin attenuated the FoxO1-induced activation of the ATGL promoter. Our data reveal that FoxO1 regulates the activity of ATGL in GMECs by binding to FKH elements located in the ATGL promoter.


Assuntos
Lipólise , Fosfatidilinositol 3-Quinases , Feminino , Humanos , Animais , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Leite/metabolismo , Ácidos Graxos/metabolismo , Transdução de Sinais , Células Epiteliais/metabolismo , Homeostase , Cabras/genética , Glândulas Mamárias Animais/metabolismo
9.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1868(10): 159376, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37516308

RESUMO

Two distinct diacylglycerol acyltransferases (DGAT1 and DGAT2) catalyze the final committed step of triacylglycerol (TG) synthesis in hepatocytes. After its synthesis in the endoplasmic reticulum (ER) TG is either stored in cytosolic lipid droplets (LDs) or is assembled into very low-density lipoproteins in the ER lumen. TG stored in cytosolic LDs is hydrolyzed by adipose triglyceride lipase (ATGL) and the released fatty acids are converted to energy by oxidation in mitochondria. We hypothesized that targeting/association of ATGL to LDs would differ depending on whether the TG stores were generated through DGAT1 or DGAT2 activities. Individual inhibition of DGAT1 or DGAT2 in Huh7 hepatocytes incubated with oleic acid did not yield differences in TG accretion while combined inhibition of both DGATs completely prevented TG synthesis suggesting that either DGAT can efficiently esterify exogenously supplied fatty acid. DGAT2-made TG was stored in larger LDs, whereas TG formed by DGAT1 accumulated in smaller LDs. Inactivation of DGAT1 or DGAT2 did not alter expression (mRNA or protein) of ATGL, the ATGL activator ABHD5/CGI-58, or LD coat proteins PLIN2 or PLIN5, but inactivation of both DGATs increased PLIN2 abundance despite a dramatic reduction in the number of LDs. ATGL was found to preferentially target to LDs generated by DGAT1 and fatty acids released from TG in these LDs were also preferentially used for fatty acid oxidation. Combined inhibition of DGAT2 and ATGL resulted in larger LDs, suggesting that the smaller size of DGAT1-generated LDs is the result of increased lipolysis of TG in these LDs.


Assuntos
Hepatócitos , Lipólise , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Triglicerídeos/metabolismo
10.
Cancer Lett ; 569: 216306, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37442366

RESUMO

Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.


Assuntos
Proteínas de Ciclo Celular , Neoplasias , Proteínas de Ciclo Celular/metabolismo , Lipase/genética , Lipase/metabolismo , Adipócitos/metabolismo , Lipólise , Fenômenos Fisiológicos Celulares
11.
Mol Metab ; 74: 101751, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37295745

RESUMO

OBJECTIVE: Glucocorticoids are one of the most commonly prescribed classes of anti-inflammatory drugs; however, chronic treatment promotes iatrogenic (drug-induced) diabetes. As part of their physiological role, glucocorticoids stimulate lipolysis to spare glucose. We hypothesized that persistent stimulation of lipolysis during glucocorticoid therapy plays a causative role in the development of iatrogenic diabetes. METHODS: Male C57BL/6J mice were given 100 µg/mL corticosterone (Cort) in the drinking water for two weeks and were fed either normal chow (TekLad 8640) or the same diet supplemented with an adipose triglyceride lipase inhibitor (Atglistatin - 2  g/kg diet) to inhibit the first step of lipolysis. RESULTS: Herein, we report for the first time that glucocorticoid administration promotes a unique state of substrate excess and energetic overload in skeletal muscle that primarily results from the rampant mobilization of endogenous fuels. Inhibiting lipolysis protected mice from Cort-induced gains in fat mass, excess ectopic lipid accrual, hyperinsulinemia, and hyperglycemia. The role lipolysis plays in Cort-mediated pathology appears to differ between tissues. Within skeletal muscle, Cort-induced lipolysis facilitated diversion of glucose-derived carbons toward the pentose phosphate and hexosamine biosynthesis pathways but contributed to <3% of the Cort-induced genomic adaptations. In contrast, Cort stimulation of lipolysis accounted for ∼35% of the genomic changes in the liver but had minimal impact on hepatic metabolites reported. CONCLUSIONS: These data support the idea that activation of lipolysis plays a causal role in the progression toward iatrogenic diabetes during glucocorticoid therapy with differential impact on skeletal muscle and liver.


Assuntos
Glucocorticoides , Resistência à Insulina , Masculino , Camundongos , Animais , Glucocorticoides/metabolismo , Lipólise/genética , Camundongos Endogâmicos C57BL , Corticosterona/farmacologia , Glucose/metabolismo , Doença Iatrogênica
12.
J Lipid Res ; 64(6): 100386, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37172691

RESUMO

Levels of circulating fatty acid binding protein 4 (FABP4) protein are strongly associated with obesity and metabolic disease in both mice and humans, and secretion is stimulated by ß-adrenergic stimulation both in vivo and in vitro. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of adipose triglyceride lipase (ATGL) and was absent from adipose tissue explants from mice specifically lacking ATGL in their adipocytes (ATGLAdpKO). Here, we find that upon activation of ß-adrenergic receptors in vivo, ATGLAdpKO mice unexpectedly exhibited significantly higher levels of circulating FABP4 as compared with ATGLfl/fl controls, despite no corresponding induction of lipolysis. We generated an additional model with adipocyte-specific deletion of both FABP4 and ATGL (ATGL/FABP4AdpKO) to evaluate the cellular source of this circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the source of elevated FABP4 levels in ATGLAdpKO mice was indeed from the adipocytes. ATGLAdpKO mice exhibited significantly elevated corticosterone levels, which positively correlated with plasma FABP4 levels. Pharmacological inhibition of sympathetic signaling during lipolysis using hexamethonium or housing mice at thermoneutrality to chronically reduce sympathetic tone significantly reduced FABP4 secretion in ATGLAdpKO mice compared with controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL, per se, is not required for in vivo stimulation of FABP4 secretion from adipocytes, which can be induced through sympathetic signaling.


Assuntos
Lipase , Lipólise , Animais , Camundongos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Lipase/genética , Lipase/metabolismo , Lipólise/fisiologia
13.
Front Endocrinol (Lausanne) ; 14: 1116136, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37139333

RESUMO

Retinal neovascular, neurodegenerative, and inflammatory diseases represented by diabetic retinopathy are the main types of blinding eye disorders that continually cause the increased burden worldwide. Pigment epithelium-derived factor (PEDF) is an endogenous factor with multiple effects including neurotrophic activity, anti-angiogenesis, anti-tumorigenesis, and anti-inflammatory activity. PEDF activity depends on the interaction with the proteins on the cell surface. At present, seven independent receptors, including adipose triglyceride lipase, laminin receptor, lipoprotein receptor-related protein, plexin domain-containing 1, plexin domain-containing 2, F1-ATP synthase, and vascular endothelial growth factor receptor 2, have been demonstrated and confirmed to be high affinity receptors for PEDF. Understanding the interactions between PEDF and PEDF receptors, their roles in normal cellular metabolism and the response the initiate in disease will be accommodating for elucidating the ways in which inflammation, angiogenesis, and neurodegeneration exacerbate disease pathology. In this review, we firstly introduce PEDF receptors comprehensively, focusing particularly on their expression pattern, ligands, related diseases, and signal transduction pathways, respectively. We also discuss the interactive ways of PEDF and receptors to expand the prospective understanding of PEDF receptors in the diagnosis and treatment of retinal diseases.


Assuntos
Doenças Retinianas , Serpinas , Humanos , Proteínas do Olho/metabolismo , Estudos Prospectivos , Doenças Retinianas/tratamento farmacológico , Serpinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Biochem Biophys Rep ; 34: 101476, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37144119

RESUMO

Nicotinamide adenine dinucleotide (NAD+) -dependent protein deacetylase SIRT1 plays an important role in the regulation of metabolism. Although the administration of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to ameliorate metabolic disorders, such as insulin resistance and glucose intolerance, the direct effect of NMN on the regulation of lipid metabolism in adipocytes remains unclear. We here investigated the effect of NMN on lipid storage in 3T3-L1 differentiated adipocytes. Oil-red O staining showed that NMN treatment reduced lipid accumulation in these cells. NMN was found to enhance lipolysis in adipocytes since the concentration of glycerol in the media was increased by NMN treatment. Western blotting and real-time RT-PCR analysis revealed that adipose triglyceride lipase (ATGL) expression at both protein and mRNA level was increased with NMN treatment in 3T3-L1 adipocytes. Whereas NMN increased SIRT1 expression and AMPK activation, an AMPK inhibitor compound C restored the NMN-dependent upregulation of ATGL expression in these cells, suggesting that NMN upregulates ATGL expression through the SIRT1-AMPK axis. NMN administration significantly decreased subcutaneous fat mass in mice on a high-fat diet. We also found that adipocyte size in subcutaneous fat was decreased with NMN treatment. Consistent with the alteration of fat mass and adipocyte size, the ATGL expression in subcutaneous fat was slightly, albeit significantly, increased with NMN treatment. These results indicate that NMN suppresses subcutaneous fat mass in diet-induced obese mice, potentially in part via the upregulation of ATGL. Unexpectedly, the reduction in fat mass as well as ATGL upregulation with NMN treatment were not observed in epididymal fat, implying that the effects of NMN are site-specific in adipose tissue. Thus, these findings provide important insights into the mechanism of NMN/NAD+ in the regulation of metabolism.

15.
J Lipid Res ; 64(5): 100355, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36934842

RESUMO

Biogenesis of lipid droplets (LDs) in various cells plays an important role in various physiological and pathological processes. However, the function of LDs in endothelial physiology and pathology is not well understood. In the present work, we investigated the formation of LDs and prostacyclin (PGI2) generation in the vascular tissue of isolated murine aortas following activation by proinflammatory factors: tumor necrosis factor (TNF), lipopolysaccharides (LPS), angiotensin II (AngII), hypoxic conditions, or oleic acid (OA). The abundance, size, and biochemical composition of LDs were characterized based on Raman spectroscopy and fluorescence imaging. We found that blockade of lipolysis by the adipose triglyceride lipase (ATGL) delayed LDs degradation and simultaneously blunted PGI2 generation in aorta treated with all tested proinflammatory stimuli. Furthermore, the analysis of Raman spectra of LDs in the isolated vessels stimulated by TNF, LPS, AngII, or hypoxia uncovered that these LDs were all rich in highly unsaturated lipids and had a negligible content of phospholipids and cholesterols. Additionally, by comparing the Raman signature of endothelial LDs under hypoxic or OA-overload conditions in the presence or absence of ATGL inhibitor, atglistatin (Atgl), we show that Atgl does not affect the biochemical composition of LDs. Altogether, independent of whether LDs were induced by pro-inflammatory stimuli, hypoxia, or OA and of whether they were composed of highly unsaturated or less unsaturated lipids, we observed LDs formation invariably associated with ATGL-dependent PGI2 generation. In conclusion, vascular LDs formation and ATGL-dependent PGI2 generation represent a universal response to vascular proinflammatory insult.


Assuntos
Epoprostenol , Ácido Oleico , Animais , Camundongos , Ácido Oleico/metabolismo , Epoprostenol/metabolismo , Gotículas Lipídicas/metabolismo , Lipopolissacarídeos/metabolismo , Lipólise , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Prostaglandinas I/metabolismo
16.
Cell Rep Methods ; 3(2): 100394, 2023 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-36936069

RESUMO

Intracellular long-chain acyl-coenzyme As (LC-acyl-CoAs) are thought to be under tight spatial and temporal controls, yet the ability to image LC-acyl-CoAs in live cells is lacking. Here, we developed a fluorescence resonance energy transfer (FRET) sensor for LC-acyl-CoAs based on the allosterically regulated interaction between α/ß hydrolase domain-containing 5 (ABHD5) and Perilipin 5. The genetically encoded sensor rapidly detects intracellular LC-acyl-CoAs generated from exogenous and endogenous fatty acids (FAs), as well as synthetic ABHD5 ligands. Stimulation of lipolysis in brown adipocytes elevated intracellular LC-acyl-CoAs in a cyclic fashion, which was eliminated by inhibiting PNPLA2 (ATGL), the major triglyceride lipase. Interestingly, inhibition of LC-acyl-CoA transport into mitochondria elevated intracellular LC-acyl-CoAs and dampened their cycling. Together, these observations reveal an intimate feedback control between LC-acyl-CoA generation from lipolysis and utilization in mitochondria. We anticipate that this sensor will be an important tool to dissect intracellular LC-acyl-CoA dynamics as well to discover novel synthetic ABHD5 ligands.


Assuntos
Acil Coenzima A , Transferência Ressonante de Energia de Fluorescência , Acil Coenzima A/metabolismo , Lipólise/fisiologia , Lipase/genética , Ácidos Graxos
17.
Mol Genet Metab Rep ; 34: 100960, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36846631

RESUMO

Primary triglyceride deposit cardiomyovasculopathy (P-TGCV), caused by a rare genetic mutation in PNPLA2 encoding adipose triglyceride lipase (ATGL), exhibits severe cardiomyocyte steatosis and heart failure. Here, we report the case of a 51-year-old man with P-TGCV homozygous for a novel PNPLA2 mutation (c.446C > G, P149R) in the catalytic domain of ATGL. Analyses of endomyocardial biopsy specimens and in vitro expression experiments showed mutant protein expression with conserved lipid binding, but reduced lipolytic activity, indicating mutation pathogenicity.

18.
Lab Invest ; 103(1): 100004, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36748188

RESUMO

Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/ß-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-ß1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.


Assuntos
Aciltransferases , Fibrilação Atrial , Lipase , Animais , Masculino , Camundongos , Angiotensina II/metabolismo , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrose , Lipase/genética , Lipase/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/genética , PPAR alfa/agonistas , PPAR alfa/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-36521736

RESUMO

Fasting and starvation were common occurrences during human evolution and accordingly have been an important environmental factor shaping human energy metabolism. Humans can tolerate fasting reasonably well through adaptative and well-orchestrated time-dependent changes in energy metabolism. Key features of the adaptive response to fasting are the breakdown of liver glycogen and muscle protein to produce glucose for the brain, as well as the gradual depletion of the fat stores, resulting in the release of glycerol and fatty acids into the bloodstream and the production of ketone bodies in the liver. In this paper, an overview is presented of our current understanding of the effects of fasting on adipose tissue metabolism. Fasting leads to reduced uptake of circulating triacylglycerols by adipocytes through inhibition of the activity of the rate-limiting enzyme lipoprotein lipase. In addition, fasting stimulates the degradation of stored triacylglycerols by activating the key enzyme adipose triglyceride lipase. The mechanisms underlying these events are discussed, with a special interest in insights gained from studies on humans. Furthermore, an overview is presented of the effects of fasting on other metabolic pathways in the adipose tissue, including fatty acid synthesis, glucose uptake, glyceroneogenesis, autophagy, and the endocrine function of adipose tissue.


Assuntos
Tecido Adiposo , Jejum , Humanos , Tecido Adiposo/metabolismo , Adipócitos/metabolismo , Lipólise , Triglicerídeos/metabolismo
20.
Anim Biotechnol ; 34(7): 3126-3134, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36306180

RESUMO

Adipose triglyceride lipase (ATGL) is the key enzyme for the degradation of triacylglycerols (TAGs). It functions in concert with other enzymes to mobilize TAG and supply fatty acids (FAs) for energy production. Dysregulated lipolysis leads to excess concentrations of circulating FAs, which may lead to destructive and lipotoxic effects to the organism. To understand the role of ATGL in mammary lipid metabolism, ATGL was overexpressed in goat mammary epithelial cells (GMECs) by using a recombinant adenovirus system. ATGL overexpression decreased lipid droplet (LD) accumulation and cellular TG content (p < 0.05) along with a decrease in the expression of the key enzyme that catalyzes the final step of TG synthesis (DGAT). Significant increases were observed in the expression of genes related to lipolysis (hormone-sensitive lipase [HSL]) and FA desaturation (SCD) by ATGL overexpression. Genes responsible for FA oxidation (PPARα), LD formation and secretion (ADRP and BTN1A1), and long-chain FA uptake (CD36) were all decreased by ATGL overexpression (p < 0.05). The primary products of TAG lipolysis, free FAs (FFAs), were notably increased in the ATGL-overexpressing cells. Taken together, our results demonstrated that ATGL activation impairs lipid formation partially through accelerating lipolysis in GMECs.


Assuntos
Lipase , Lipólise , Animais , Lipólise/fisiologia , Lipase/genética , Lipase/metabolismo , Gotículas Lipídicas/metabolismo , Cabras/metabolismo , Ácidos Graxos , Células Epiteliais/metabolismo
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