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2.
Cell Metab ; 34(11): 1824-1842.e9, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36243006

RESUMO

During mammalian energy homeostasis, the glucagon receptor (Gcgr) plays a key role in regulating both glucose and lipid metabolisms. However, the mechanisms by which these distinct signaling arms are differentially regulated remain poorly understood. Using a Cy5-glucagon agonist, we show that the endosomal protein Vps37a uncouples glucose production from lipid usage downstream of Gcgr signaling by altering intracellular receptor localization. Hepatocyte-specific knockdown of Vps37a causes an accumulation of Gcgr in endosomes, resulting in overactivation of the cAMP/PKA/p-Creb signaling pathway to gluconeogenesis without affecting ß-oxidation. Shifting the receptor back to the plasma membrane rescues the differential signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic effects. Importantly, since Vps37a knockdown in animals fed with a high-fat diet leads to hyperglycemia, although its overexpression reduces blood glucose levels, these data reveal a contribution of endosomal signaling to metabolic diseases that could be exploited for treatments of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Receptores de Glucagon , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Endossomos/metabolismo , Glucagon/metabolismo , Glucose/metabolismo , Lipídeos , Fígado/metabolismo , Mamíferos/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Glucagon/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo
3.
Nat Metab ; 1(10): 1009-1026, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-32694843

RESUMO

Non-alcoholic fatty liver disease (NAFLD) represents a key feature of obesity-related type 2 diabetes with increasing prevalence worldwide. To our knowledge, no treatment options are available to date, paving the way for more severe liver damage, including cirrhosis and hepatocellular carcinoma. Here, we show an unexpected function for an intracellular trafficking regulator, the small Rab GTPase Rab24, in mitochondrial fission and activation, which has an immediate impact on hepatic and systemic energy homeostasis. RAB24 is highly upregulated in the livers of obese patients with NAFLD and positively correlates with increased body fat in humans. Liver-selective inhibition of Rab24 increases autophagic flux and mitochondrial connectivity, leading to a strong improvement in hepatic steatosis and a reduction in serum glucose and cholesterol levels in obese mice. Our study highlights a potential therapeutic application of trafficking regulators, such as RAB24, for NAFLD and establishes a conceptual functional connection between intracellular transport and systemic metabolic dysfunction.


Assuntos
Glicemia/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Adiposidade , Adulto , Animais , Autofagia , Colesterol/sangue , Feminino , Homeostase , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Regulação para Cima , Proteínas rab de Ligação ao GTP/genética
4.
Dev Cell ; 47(2): 205-221.e7, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30352176

RESUMO

Lipid metabolism is highly compartmentalized between cellular organelles that dynamically adapt their compositions and interactions in response to metabolic challenges. Here, we investigate how diet-induced hepatic lipid accumulation, observed in non-alcoholic fatty liver disease (NAFLD), affects protein localization, organelle organization, and protein phosphorylation in vivo. We develop a mass spectrometric workflow for protein and phosphopeptide correlation profiling to monitor levels and cellular distributions of ∼6,000 liver proteins and ∼16,000 phosphopeptides during development of steatosis. Several organelle contact site proteins are targeted to lipid droplets (LDs) in steatotic liver, tethering organelles orchestrating lipid metabolism. Proteins of the secretory pathway dramatically redistribute, including the mis-localization of the COPI complex and sequestration of the Golgi apparatus at LDs. This correlates with reduced hepatic protein secretion. Our systematic in vivo analysis of subcellular rearrangements and organelle-specific phosphorylation reveals how nutrient overload leads to organellar reorganization and cellular dysfunction.


Assuntos
Fígado Gorduroso/fisiopatologia , Gotículas Lipídicas/fisiologia , Organelas/fisiologia , Animais , Dieta , Dieta Hiperlipídica , Complexo de Golgi/fisiologia , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Lipídeos/fisiologia , Fígado , Espectrometria de Massas/métodos , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais , Nutrientes/metabolismo , Organelas/efeitos dos fármacos , Fosforilação , Transporte Proteico , Proteômica/métodos , Via Secretória
5.
Sci Rep ; 7(1): 4023, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28642463

RESUMO

Liver cells communicate with the extracellular environment to take up nutrients via endocytosis. Iron uptake is essential for metabolic activities and cell homeostasis. Here, we investigated the role of the endocytic system for maintaining iron homeostasis. We specifically depleted the small GTPase Rab5 in the mouse liver, causing a transient loss of the entire endo-lysosomal system. Strikingly, endosome depletion led to a fast reduction of hepatic iron levels, which was preceded by an increased abundance of the iron exporter ferroportin. Compensatory changes in livers of Rab5-depleted mice include increased expression of transferrin receptor 1 as well as reduced expression of the iron-regulatory hormone hepcidin. Serum iron indices (serum iron, free iron binding capacity and total iron binding capacity) in Rab5-KD mice were increased, consistent with an elevated splenic and hepatic iron export. Our data emphasize the critical importance of the endosomal compartments in hepatocytes to maintain hepatic and systemic iron homeostasis in vivo. The short time period (between day four and five) upon which these changes occur underscore the fast dynamics of the liver iron pool.


Assuntos
Endossomos/metabolismo , Hepatócitos/metabolismo , Homeostase , Ferro/metabolismo , Lisossomos/metabolismo , Animais , Transporte Biológico , Biomarcadores , Regulação da Expressão Gênica , Fígado/metabolismo , Camundongos , Baço/metabolismo
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