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Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease.
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The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride (triacylglycerol: TAG) turnover. Hypoxia in obese adipose tissue due to hypertrophic adipocytes results in excess deposition of extracellular matrix (ECM) components. Cluster of differentiation (CD) 44, as the main receptor of the extracellular matrix component regulates cell-cell and cell-matrix interactions including diet-induced insulin resistance. Excess TAGs, sterols, and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets (LDs). Once LDs are formed, they grow up because of the excessive amount of intracellular FFA stored and reach a final size. The ratio of FFA turnover/lipolysis decreases significantly with increases in the degree of obesity. Dysfunctional adipose tissue is unable to expand further to store excess dietary lipids, increased fluxes of plasma FFAs lead to ectopic fatty acid deposition and lipotoxicity. Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. Adipocyte death is a prerequisite for the transition from hypertrophic to hyperplastic obesity. Increased adipocyte number in obesity has life-long effects on white adipose tissue mass. The positive correlation between the adipose tissue volume and magnetic resonance imaging proton density fat fraction estimation is used for characterization of the obesity phenotype, as well as the risk stratification and selection of appropriate treatment strategies. In obese patients with type 2 diabetes, visceral adipocytes exposed to chronic/intermittent hyperglycemia develop a new microRNAs' (miRNAs') expression pattern. Visceral preadipocytes memorize the effect of hyperglycemia via changes in miRNAs' expression profile and contribute to the progression of diabetic phenotype. Nonsteroidal anti-inflammatory drugs, metformin, and statins can be beneficial in treating the local or systemic consequences of white adipose tissue inflammation. Rapamycin inhibits leptin-induced LD formation. Collectively, in this chapter, the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of LD interactions with the other cellular organelles are reviewed. Furthermore, clinical perspective of fat cell turnover in obesity is also debated.
Assuntos
Adipócitos , Lipólise , Obesidade , Humanos , Obesidade/metabolismo , Obesidade/patologia , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Metabolismo dos Lipídeos , Adipogenia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Resistência à InsulinaRESUMO
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.
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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/metabolismoRESUMO
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.
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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 C57BLRESUMO
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.
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Proteínas de Ciclo Celular , Neoplasias , Proteínas de Ciclo Celular/metabolismo , Lipase/genética , Lipase/metabolismo , Adipócitos/metabolismo , Lipólise , Fenômenos Fisiológicos CelularesRESUMO
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.
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Doenças Retinianas , Serpinas , Humanos , Proteínas do Olho/metabolismo , Estudos Prospectivos , Doenças Retinianas/tratamento farmacológico , Serpinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The hypoxic state of the tumor microenvironment leads to reprogramming lipid metabolism in tumor cells. Adipose triglyceride lipase, also known as patatin-like phospholipase= domain-containing protein 2 and Adipose triglyceride lipase (ATGL), as an essential lipid metabolism-regulating enzyme in cells, is regulated accordingly under hypoxia induction. However, studies revealed that ATGL exhibits both tumor-promoting and tumor-suppressing effects, which depend on the cancer cell type and the site of tumorigenesis. For example, elevated ATGL expression in breast cancer is accompanied by enhanced fatty acid oxidation (FAO), enhancing cancer cells' metastatic ability. In prostate cancer, on the other hand, tumor activity tends to be negatively correlated with ATGL expression. This review outlined the regulation of ATGL-mediated lipid metabolism pathways in tumor cells, emphasizing the Hypoxia-inducible factors 1 (HIF-1)/Hypoxia-inducible lipid droplet-associated (HIG-2)/ATGL axis, peroxisome proliferator-activated receptor (PPAR)/G0/G1 switch gene 2 (G0S2)/ATGL axis, and fat-specific protein 27 (FSP-27)/Early growth response protein 1 (EGR-1)/ATGL axis. In the light of recent research on different cancer types, the role of ATGL on tumorigenesis, tumor proliferation, and tumor metastasis was systemically reviewed.
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Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although cachexia is a syndrome of adipose loss and obesity is a disease of adipose excess, both pathologies demonstrate increases in circulating levels of IL-6 family cytokines, ß-adrenergic signaling, and adipocyte lipolysis. While ß-adrenergic-stimulated adipocyte lipolysis is well described, there is limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to adipocyte lipolysis under pathologic conditions. Here, we set out to compare adipocyte lipolysis signaling by cancer cachexia-associated IL-6 family cytokines (IL-6 and LIF) to that of the ß-adrenergic agonist isoproterenol. Unlike isoproterenol, the IL-6 family of cytokines required JAK/STAT3-dependent transcriptional changes to induce adipocyte lipolysis. Furthermore, cachexia-associated cytokines that used STAT3 to induce lipolysis were primarily dependent on the lipase ATGL and its cofactor CGI-58 rather than lipases HSL and MAGL. Finally, administration of JAK but not ß-adrenergic inhibitors suppressed adipose STAT3 phosphorylation and associated adipose wasting in a murine model of cancer cachexia characterized by increased systemic IL-6 family cytokine levels. Combined, our results demonstrate how the IL-6 family of cytokines diverge from ß-adrenergic signals by employing JAK/STAT3-driven transcriptional changes to promote adipocyte ATGL/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia.
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Prolyl isomerase Pin1 is associated with various substrates and controls their functions through the isomerization of proline. Interestingly, a high fat diet increases Pin1 levels in adipose tissues. Accordingly, we investigated how Pin1 regulates energy metabolism in adipose tissues. Currently, adipocytes are divided into three types with distinct features. White adipocytes (WATs) store energy as triglycerides under fed conditions and release non-esterified fatty acids and glycerol through lipolysis while fasting. Brown and beige adipocytes, which exist in subcutaneous fat (scWAT), promote energy consumption through thermogenesis. We found that Pin1 impacts both thermogenesis and lipolysis upon interaction with distinct substrates. When mice were exposed to cold stress, both brown adipose tissues (BAT) and scWAT from adipocyte-specific Pin1 knockout (KO) mice showed higher expression levels of thermogenic genes in comparison to those from wild-type mice. Furthermore, we observed that Pin1 binds to the PRDM16 transcriptional cofactor, a major contributor to thermogenic programs, and promotes its degradation. Therefore, Pin1 suppresses thermogenesis. Meanwhile, in white adipocytes, Pin1 is involved in lipolysis. Pin1 deficiency enhanced lipolysis activity in epididymal WAT (epiWAT), but not in scWAT and BAT. In epiWAT, Pin1 interacts with adipose triglyceride lipase (ATGL) which is a rate-limiting enzyme for lipolysis, and downregulates ATGL levels. Finally, adipocyte-specific Pin1 KO mice have less body weight and better glucose metabolism under high fat diet conditions. These observations indicate that Pin1 is involved in the function of adipocytes through its association with PRDM16 and ATGL. Pin1 inhibitors could have therapeutic applications in the treatment of obesity.
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Peptidilprolil Isomerase , Termogênese , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Camundongos , Camundongos Knockout , Músculos/metabolismo , Peptidilprolil Isomerase/genética , Peptidilprolil Isomerase/metabolismo , Termogênese/genética , Fatores de Transcrição/genéticaRESUMO
Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.
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Proteínas de Transporte/genética , Transportador de Glucose Tipo 1/genética , Glucose/metabolismo , Lipase/genética , Lipólise/genética , Tiorredoxinas/genética , Células 3T3-L1 , Adipócitos/enzimologia , Adipócitos/metabolismo , Animais , AMP Cíclico/metabolismo , AMP Cíclico/farmacologia , Glucose/genética , Humanos , Ácido Láctico/biossíntese , Ácido Láctico/metabolismo , Camundongos , Proteólise/efeitos dos fármacos , Esterol Esterase/genéticaRESUMO
The G protein-coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in WT mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat and high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity because of downregulation of lipolytic enzymes such as adipose triglyceride lipase and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of adipose triglyceride lipase in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders.
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Inflamação/genética , Obesidade/genética , Osteocalcina/genética , Receptores Acoplados a Proteínas G/genética , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Teste de Tolerância a Glucose , Humanos , Inflamação/patologia , Insulina/genética , Resistência à Insulina/genética , Lipase/genética , Lipólise/genética , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologiaRESUMO
BACKGROUND: Lipolysis is essential for the supply of nutrients during fasting, the control of body weight, and remodeling of white adipose tissues and thermogenesis. In the obese state, lipolysis activity and the expression of adipose triglyceride lipase (ATGL), a rate-limiting enzyme, is suppressed. However, the mechanism underlying the regulation of ATGL remains largely unknown. We previously reported that a high-fat diet obviously increases protein levels of the prolyl isomerase, Pin1, in epididymal white adipose tissue (epiWAT) of mice and that Pin1 KO mice are resistant to developing obesity. RESULTS: The present study found that deletion of the Pin1 gene in epiWAT upregulated lipolysis and increased ATGL protein expression by ~2-fold. In addition, it was demonstrated that Pin1 directly associated with ATGL and enhanced its degradation through the ubiquitin proteasome system. Indeed, Pin1 overexpression decreased ATGL expression levels, whereas Pin1 knockdown by siRNA treatment upregulated ATGL protein levels without altering mRNA levels. Moreover, under a high fat diet (HFD)-fed condition, adipocyte-specific Pin1 KO (adipoPin1 KO) mice had 2-fold increase lipolytic activity and upregulated ß-oxidation-related gene expressions. These mice also gained less body weight, and had better glucose metabolism according to the results of glucose and insulin tolerance tests. CONCLUSION: Taken together, these results showed that Pin1 directly interacted with and degraded ATGL via a ubiquitin-proteasome system, consequently causing the downregulation of lipolysis. Therefore, Pin1 could be considered a target for the treatment of dyslipidemia and related disorders.
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Tecido Adiposo/metabolismo , Regulação da Expressão Gênica , Lipase/metabolismo , Lipólise/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Obesidade/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Peptidilprolil Isomerase de Interação com NIMA/genéticaRESUMO
The ability of mammals to store and draw on fat reserves has been a driving force throughout evolution in an environment with intermittent nutrient availability. The discovery of adipose triglyceride lipase (ATGL) as a triglyceride lipase provided a heightened understanding of the mechanisms governing mobilization of fat reserves from adipose tissue. ATGL catalyses the initial step in adipose triglyceride lipolysis, working in concert with other enzymes to mobilize triglyceride for energy production. In addition to the role of ATGL in adipose tissue triglyceride mobilization, ATGL plays crucial roles in regulating lipid homeostasis in other tissues. These roles have been characterized primarily using transgenic mice with tissue-specific ATGL ablation. For example, the global ATGL knockout induces a severe cardiac defect that results in premature mortality that is mimicked by inducible cardiomyocyte-specific ATGL knockout. Global- and adipose-specific ATGL ablation induces a whole-body shift from lipid metabolism to glucose metabolism to satisfy metabolic demand primarily facilitated by an increase in glucose uptake by skeletal muscle. Generation of liver-specific ATGL knockouts has implicated hepatic lipolysis as a critical component of normal liver function. Analysis of ß-cell ATGL knockouts implicates the necessity of pancreatic ATGL in insulin secretion. The objective of this review is to discuss the contributions of ATGL to systemic lipid- and glucose-homeostasis discovered through the study of transgenic mice.
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Tecido Adiposo/metabolismo , Glucose/metabolismo , Glicólise/genética , Lipase/genética , Lipólise/genética , Triglicerídeos/metabolismo , Animais , Expressão Gênica , Homeostase/genética , Insulina/metabolismo , Lipase/deficiência , Lipase/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Pâncreas/metabolismoRESUMO
The aims of the present study were to clone the full-length cDNA of adipose triglyceridelipase (ATGL) and to analyze its expression after lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α). The cDNA obtained covered 1801 bp with an open reading frame of 1500 bp encoding 499 amino acids. Sequence alignment and phylogenetic analysis show the best identity with Cyprinus carpio (86%). The ATGL protein shared a highly conserved 169-amino acid patatin domain, containing a glycine-rich motif, an active serine hydrolase motif, and an aspartic active site. The highest ATGL expression was observed in the liver followed by muscle, whereas relatively low values were detected in the brain and adipose. TNF-α is regarded as an important factor in regulating fat metabolism. Here, LPS was used to induce TNF-α in vivo to verify whether TNF-α can affect ATGL expression. TNF-α expression in liver and muscle is increased and remains unchanged in adipose tissue and brain. The variation of ATGL activity is consistent with that of TNF-α gene expression. Next, we explored the mechanism by which LPS-induced TNF-α mediates the mRNA expression of ATGL in the liver and muscle. For liver, the mRNA levels of c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), Sirtuin 1 (SIRT1), and AMP-activated protein kinase (AMPK) were increased by LPS-induced TNF-α. Differencing from the situation in the liver, there was a near-significant decrease trend in the expression of SIRT1 in muscle. Those results indicated that the ATGL gene of blunt snout bream shared a high similarity with the other vertebrates. The expression level of ATGL in tissues with high-fat content was intended to be high. LPS can induce ATGL expression perhaps related to TNF-α.
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Carpas/metabolismo , Proteínas de Peixes/metabolismo , Lipase/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Carpas/genética , Carpas/crescimento & desenvolvimento , Clonagem Molecular , Proteínas de Peixes/genética , Regulação Enzimológica da Expressão Gênica , Lipase/genética , Lipopolissacarídeos/metabolismo , Especificidade de Órgãos , Filogenia , Homologia de Sequência , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Neutral lipid storage disease with myopathy (NLSDM) is a rare metabolic myopathy occurring owing to mutations in the patatin like phospholipase domain containing 2 (PNPLA2) gene. Till date, less than 50 patients with PNPLA2 mutations have been reported. In this study, we describe the clinical, pathological, and genetic findings, and muscle magnetic resonance imaging (MRI) changes in four Chinese patients with NLSDM. PATIENTS AND METHODS: Peripheral blood smears were stained using Wright's stain. Muscle biopsies, muscle MRI, and sequence analysis of PNPLA2 gene were performed. RESULTS: All patients exhibited slowly progressive myopathy during adulthood. Cardiomyopathy, sensorineural hearing loss, hepatic adipose infiltration, and hypertriglyceridemia were observed in some patients. Jordan's anomaly was detected in the blood smears of all patients. Muscle biopsies revealed the presence of massive lipid droplets and rimmed vacuoles in two patients. MR images of the lower lumbar, pelvis, and lower extremities showed the involvement of posterior compartment muscles. The anterior compartment muscles were found to be less affected. Gene analysis for PNPLA2 revealed an identical homozygous mutation c.757â¯+â¯1Gâ¯>â¯T in all patients. CONCLUSION: Patients with NLSDM display clinical heterogeneities despite sharing the same mutation (c.757â¯+â¯1Gâ¯>â¯T) of the PNPLA2 gene, may suggest a founder effect in the region.
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Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Musculares/genética , Mutação/genética , Adulto , Povo Asiático , Biópsia , China , Feminino , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/patologiaRESUMO
The breakdown of stored fat deposits into its components is a highly regulated process that maintains plasma levels of free fatty acids to supply energy to cells. Insulin-mediated transcription of Atgl, the enzyme that mediates the rate-limiting step in lipolysis, is a key point of this regulation. Under conditions such as obesity or insulin resistance, Atgl transcription is often misregulated, which can contribute to overall disease progression. The mechanisms by which Atgl is induced during adipogenesis are not fully understood. We utilized computational approaches to identify putative transcriptional regulatory elements in Atgl and then tested the effect of these elements and the transcription factors that bind to them in cultured preadipocytes and mature adipocytes. Here we report that Atgl is down-regulated by the basal transcription factor Sp1 in preadipocytes and that the magnitude of down-regulation depends on interactions between Sp1 and peroxisome proliferator-activated receptor γ (PPARγ). In mature adipocytes, when PPARγ is abundant, PPARγ abrogated transcriptional repression by Sp1 at the Atgl promoter and up-regulated Atgl mRNA expression. Targeting the PPARγ-Sp1 interaction could be a potential therapeutic strategy to restore insulin sensitivity by modulating Atgl levels in adipocytes.
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Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Lipase/genética , PPAR gama/metabolismo , Fator de Transcrição Sp1/metabolismo , Transcrição Gênica , Células 3T3-L1 , Animais , Linhagem Celular , Regulação para Baixo , Células HEK293 , Humanos , Lipase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese Sítio-DirigidaRESUMO
The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. Inhibition of adipose triglyceride lipase leads to an accumulation of triglyceride, whereas inhibition of hormone-sensitive lipase leads to the accumulation of diacylglycerol. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride turnover. Excess triacylglycerols (TAGs), sterols and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets. Following the release of lipid droplets from endoplasmic reticulum, cytoplasmic lipid droplets increase their volume either by local TAG synthesis or by homotypic fusion. The number and the size of lipid droplet distribution is correlated with obesity. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome-dependent caspase-1 activation in hypertrophic adipocytes induces obese adipocyte death by pyroptosis. Actually adipocyte death may be a prerequisite for the transition from hypertrophic to hyperplastic obesity. Major transcriptional factors, CCAAT/enhancer-binding proteins beta and delta, play a central role in the subsequent induction of critical regulators, peroxisome-proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha and sterol regulatory element-binding protein 1, in the transcriptional control of adipogenesis in obesity.Collectively, in this chapter the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of lipid droplet interactions with the other cellular organelles are reviewed. Furthermore, in addition to lipid droplet growth, the functional link between the adipocyte-specific lipid droplet-associated protein and fatty acid turn-over is also debated.
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Adipócitos/fisiologia , Ácidos Graxos/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Adipogenia/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Morte Celular/fisiologia , Humanos , Lipídeos/fisiologia , Triglicerídeos/metabolismoRESUMO
In liver steatosis (i.e. fatty liver), hepatocytes accumulate many large neutral lipid storage organelles known as lipid droplets (LDs). LDs are important in the maintenance of energy homeostasis, but the signaling mechanisms that stimulate LD metabolism in hepatocytes are poorly defined. In adipocytes, catecholamines target the ß-adrenergic (ß-AR)/cAMP pathway to activate cytosolic lipases and induce their recruitment to the LD surface. Therefore, the goal of this study was to determine whether hepatocytes, like adipocytes, also undergo cAMP-mediated lipolysis in response to ß-AR stimulation. Using primary rat hepatocytes and human hepatoma cells, we found that treatment with the ß-AR agent isoproterenol caused substantial LD loss via activation of cytosolic lipases adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). ß-Adrenergic stimulation rapidly activated PKA, which led to the phosphorylation of ATGL and HSL and their recruitment to the LD surface. To test whether this ß-AR-dependent lipolysis pathway was altered in a model of alcoholic fatty liver, primary hepatocytes from rats fed a 6-week EtOH-containing Lieber-DeCarli diet were treated with cAMP agonists. Compared with controls, EtOH-exposed hepatocytes showed a drastic inhibition in ß-AR/cAMP-induced LD breakdown and the phosphorylation of PKA substrates, including HSL. This observation was supported in VA-13 cells, an EtOH-metabolizing human hepatoma cell line, which displayed marked defects in both PKA activation and isoproterenol-induced ATGL translocation to the LD periphery. In summary, these findings suggest that ß-AR stimulation mobilizes cytosolic lipases for LD breakdown in hepatocytes, and perturbation of this pathway could be a major consequence of chronic EtOH insult leading to fatty liver.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , AMP Cíclico/agonistas , Fígado Gorduroso Alcoólico/metabolismo , Hepatócitos/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Células Cultivadas , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Fígado Gorduroso Alcoólico/patologia , Feminino , Hepatócitos/citologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lipase/química , Lipase/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Masculino , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Receptores Adrenérgicos beta/química , Esterol Esterase/química , Esterol Esterase/metabolismoRESUMO
Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial for maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened life span, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RIα and RIIß via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimologia , Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Metabolismo dos Lipídeos/fisiologia , Células 3T3-L1 , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , CamundongosRESUMO
Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities.