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1.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1869(3): 159461, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38272177

RESUMO

ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation. To better understand the role of intracellular ANGPTL8 in adipocytes and assess whether it may play a role in adipocyte differentiation, we knocked down its expression in normal mouse subcutaneous preadipocytes. ANGPTL8 knockdown reduced adipocyte differentiation, cellular TG accumulation and also isoproterenol-stimulated lipolysis at day 7 of differentiation. RNA-Seq analysis of ANGPTL8 siRNA or control siRNA transfected SC preadipocytes on days 0, 2, 4 and 7 of differentiation showed that ANGPTL8 knockdown impeded the early (day 2) expression of adipogenic and insulin signaling genes, PPARγ, as well as genes related to extracellular matrix and NF-κB signaling. Insulin mediated Akt phosphorylation was reduced at an early stage during adipocyte differentiation. This study based on normal primary cells shows that ANGPTL8 has intracellular actions in addition to effects in the extracellular space, like modulating LPL activity. Preadipocyte ANGPTL8 expression modulates their differentiation possibly via changes in insulin signaling gene expression.


Assuntos
Adipogenia , Insulina , Camundongos , Animais , Diferenciação Celular/genética , Adipogenia/genética , Transdução de Sinais , RNA Interferente Pequeno , Proteína 8 Semelhante a Angiopoietina
2.
Nat Commun ; 14(1): 5214, 2023 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-37626039

RESUMO

Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.


Assuntos
Proteínas de Caenorhabditis elegans , Envelhecimento Saudável , Animais , Glicogênio , Fosfatos , Proteínas Quinases Ativadas por AMP/genética , Caenorhabditis elegans/genética , Glicerol , Monoéster Fosfórico Hidrolases , Autofagia/genética , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos
3.
Mol Metab ; 66: 101609, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36198384

RESUMO

OBJECTIVE: Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a "glycerol shunt", a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. METHODS: We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16-20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. RESULTS: LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. CONCLUSIONS: The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.


Assuntos
Glicerol , Hiperglicemia , Monoéster Fosfórico Hidrolases , Animais , Masculino , Camundongos , Glucose/metabolismo , Glicerol/metabolismo , Glicogênio/metabolismo , Hiperglicemia/metabolismo , Fígado/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Triglicerídeos/metabolismo
4.
Nat Commun ; 13(1): 177, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017476

RESUMO

Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.


Assuntos
Adaptação Fisiológica/genética , Caenorhabditis elegans/genética , Glicerofosfatos/metabolismo , Proteínas de Helminto/genética , Longevidade/genética , Monoéster Fosfórico Hidrolases/genética , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Restrição Calórica , Ingestão de Alimentos/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Glucose/farmacologia , Glicerol/metabolismo , Glicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Proteínas de Helminto/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Concentração Osmolar , Monoéster Fosfórico Hidrolases/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Estresse Fisiológico/genética
5.
Am J Physiol Endocrinol Metab ; 319(1): E117-E132, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32369418

RESUMO

One of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Adipose triacylglycerol lipase (ATGL) and hormone-sensitive lipase (HSL) are critical lipolytic enzymes, and their phosphorylation generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds. Although we previously identified essential roles of the 14-3-3ζ isoform in murine adipogenesis, the presence of 14-3-3 protein binding sites on ATGL and HSL suggests that 14-3-3ζ could also influence mature adipocyte processes like lipolysis. Here we demonstrate that 14-3-3ζ is necessary for lipolysis in male mice and fully differentiated 3T3-L1 adipocytes, as depletion of 14-3-3ζ significantly impaired glycerol and free fatty acid (FFA) release. Unexpectedly, reducing 14-3-3ζ expression was found to significantly impact adipocyte maturity, as observed by reduced abundance of peroxisome proliferator-activated receptor (PPAR)γ2 protein and expression of mature adipocyte genes and those associated with de novo triglyceride synthesis and lipolysis. The impact of 14-3-3ζ depletion on adipocyte maturity was further examined with untargeted lipidomics, which revealed that reductions in 14-3-3ζ abundance promoted the acquisition of a lipidomic signature that resembled undifferentiated preadipocytes. Collectively, these findings reveal a novel aspect of 14-3-3ζ in adipocytes, as reducing 14-3-3ζ was found to have a negative effect on adipocyte maturity and adipocyte-specific processes like lipolysis.


Assuntos
Proteínas 14-3-3/genética , Adipócitos/metabolismo , Adipogenia/genética , Lipólise/genética , Proteínas 14-3-3/metabolismo , Células 3T3-L1 , Animais , Diferenciação Celular , Ácidos Graxos não Esterificados/metabolismo , Glicerol/metabolismo , Lipase/genética , Lipase/metabolismo , Lipidômica , Masculino , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Esterol Esterase/genética , Esterol Esterase/metabolismo
6.
Pharmacol Res ; 139: 199-206, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30453034

RESUMO

Since their initial characterization as abundant brain proteins more than 5 decades ago, a resurgence into understanding the cellular functions of 14-3-3 proteins has emerged. While one of the earliest functions attributed to this eukaryotic scaffold protein family was the activation of enzymes involved in catecholamine and serotonin biosynthesis, 14-3-3 proteins have since been implicated in the regulation of several cellular processes including cell-cycle control, apoptosis, and metabolism. Moreover, increasing lines of evidence demonstrate links between changes in 14-3-3 protein function and the pathogenesis of chronic diseases. As a result, this has raised the question of whether 14-3-3 proteins represent viable targets for pharmacological intervention against diseases such as obesity, diabetes and cancer. In addition to providing an overview of the 14-3-3 protein family, we will discuss their connections to metabolism and metabolic diseases. We will also elaborate on the potential of targeting 14-3-3 proteins, as well as components of their interactomes, for developing novel therapies for treating metabolic diseases, including diabetes and obesity.


Assuntos
Proteínas 14-3-3/metabolismo , Doenças Metabólicas/metabolismo , Animais , Humanos , Doenças Metabólicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Obesidade/metabolismo
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