RESUMO
Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell types to meet these increasing functional needs. Dysregulation of the UPR leads to the development of the disease. The UPR and ER stress are involved in several human conditions, such as chronic inflammation, neurodegeneration, metabolic syndrome, and cancer. Furthermore, potent and specific compounds that target the UPR pathway are under development as future therapies. The focus of this review is to thoroughly describe the effects of both internal and external stressors on the ER in asthma. Furthermore, we discuss how the UPR signaling pathway is activated in the lungs to overcome cellular damage. We also present an overview of the pathogenic mechanisms, with a brief focus on potential strategies for pharmacological interventions.
Assuntos
Asma/patologia , Neoplasias/patologia , Resposta a Proteínas não Dobradas/fisiologia , Animais , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Transdução de Sinais/fisiologiaRESUMO
The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D.
Assuntos
Peso Corporal/genética , Diabetes Mellitus Tipo 1/genética , Dieta Hiperlipídica , Predisposição Genética para Doença/genética , Obesidade/genética , Proteínas Repressoras/genética , Animais , Feminino , Interação Gene-Ambiente , Masculino , Camundongos , Camundongos Transgênicos , Proibitinas , Fatores SexuaisRESUMO
Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.
Assuntos
Infecções por Arbovirus/genética , Infecções por Arbovirus/patologia , Arbovírus/patogenicidade , Interações Hospedeiro-Patógeno , Resposta a Proteínas não Dobradas , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Vetores Aracnídeos/virologia , Infecções por Arbovirus/epidemiologia , Infecções por Arbovirus/virologia , Arbovírus/fisiologia , Autofagia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Regulação da Expressão Gênica , Humanos , Insetos Vetores/virologia , Mamíferos/virologia , Transdução de Sinais , Zoonoses/epidemiologia , Zoonoses/transmissão , Zoonoses/virologiaRESUMO
Simultaneous upregulation of transglutaminase 2 (TG2) and epidermal growth factor receptor (EGFR) have been reported in a number of systems. Moreover, TG2 has been identified as a downstream target gene for EGF/EGFR. However, it is not known whether the relationship between EGFR and TG2 is only one-way or collaborative. Using embryonic fibroblasts derived from TG2 null mice (MEF(tg2-/-)), co-overexpressing native TG2 and EGFR, here we report that TG2 differentially regulates EGFR protein in the presence and absence of EGF. In the absence of EGF, TG2 facilitates EGFR downregulation whereas in the presence of EGF, TG2 has opposite effect on EGFR and facilitates Akt phosphorylation. TG2 mediated ligand-independent downregulation of EGFR was not observed in MEF(tg2-/-) cells overexpressing Ser212Ala phospho mutant form of TG2 suggesting a role of TG2 phosphorylation in this process. However, similar to native TG2, Ser212Ala-TG2 mutant was also able to attenuate ligand-dependent down regulation of EGFR in MEF(tg2-/-) cells. Interestingly, overexpression of Ser216Ala-TG2 mutant led to downregulation of EGFR in MEF(tg2-/-) cells irrespective of the ligand. These results were further confirmed in breast cancer cells expressing high levels of EGFR. Collectively, data presented here suggests that the relationship between EGFR and TG2 is collaborative and phosphorylation of TG2 play a key role in it. Phospho mutant forms of TG2 reported in this study may be utilized as a part of a novel strategy to downregulate EGFR in cancers with enhanced EGFR signaling.
Assuntos
Receptores ErbB/biossíntese , Proteínas de Ligação ao GTP/biossíntese , Transglutaminases/biossíntese , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Receptores ErbB/antagonistas & inibidores , Feminino , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Camundongos , Camundongos Mutantes , Mutação , Fosforilação , Proteína 2 Glutamina gama-Glutamiltransferase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transglutaminases/genética , Transglutaminases/metabolismoRESUMO
BACKGROUND: Transglutaminase 2 (TG2) and its phosphorylation have been consistently found to be upregulated in a number of cancer cell types. At the molecular level, TG2 has been associated with the activation of nuclear factor-kappa B (NF-κB), protein kinase B (PKB/Akt) and in the downregulation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). However, the underlying mechanism involved is not known. We have reported that protein kinase A (PKA) induced phosphorylation of TG2 at serine-216 (Ser(216)) regulates TG2 function and facilitates protein-protein interaction. However, the role of TG2 phosphorylation in the modulation of NF-κB, Akt and PTEN is not explored. METHODS: In this study we have investigated the effect of TG2 phosphorylation on NF-κB, Akt and PTEN using embryonic fibroblasts derived from TG2 null mice (MEF(tg2-/-)) overexpressing native TG2 or mutant-TG2 (m-TG2) lacking Ser(216) phosphorylation site with and without dibutyryl cyclic-AMP (db-cAMP) stimulation. Functional consequences on cell cycle and cell motility were determined by fluorescence activated cell sorting (FACS) analysis and cell migration assay respectively. RESULTS: PKA activation in TG2 overexpressing MEF(tg2-/-) cells resulted in an increased activation of NF-κB and Akt phosphorylation in comparison to empty vector transfected control cells as determined by the reporter-gene assay and immunoblot analysis respectively. These effects were not observed in MEF(tg2-/-) cells overexpressing m-TG2. Similarly, a significant downregulation of PTEN at both, the mRNA and protein levels were found in cells overexpressing TG2 in comparison to empty vector control and m-TG2 transfected cells. Furthermore, Akt activation correlated with the simultaneous activation of NF-κB and a decrease in PTEN suggesting that the facilitatory effect of TG2 on Akt activation occurs in a PTEN-dependent manner. Similar results were found with MCF-7 and T-47D breast cancer cells overexpressing TG2 and m-TG2 further supporting the role of TG2 phosphorylation in NF-κB activation and in the downregulation of PTEN. CONCLUSIONS: Collectively, these data suggest that phosphorylation of TG2 at Ser(216) plays a role in TG2 mediated activation of NF-κB, Akt and in the downregulation of PTEN. Blocking TG2 phosphorylation may provide a novel strategy to attenuate NF-κB activation and downregulation of PTEN in TG2 overexpressing cancers.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , NF-kappa B/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Serina/metabolismo , Transglutaminases/metabolismo , Animais , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação para Baixo , Proteínas de Ligação ao GTP/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , PTEN Fosfo-Hidrolase/genética , Fosforilação , Proteína 2 Glutamina gama-Glutamiltransferase , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologia , Transglutaminases/genéticaRESUMO
Hyperglycemia induced increased posttranslational modification of proteins by O-linked-ß-N-acetyl glucosamine (O-GlcNAcylation) and mitochondrial dysfunction has been independently implicated in the development of insulin resistance. It is not known whether repertoire of O-GlcNAcylated proteins includes mitochondrial proteins and their altered O-GlcNAcylation impinges on their phosphorylation mediated normal functioning thus contribute to mitochondrial dysfunction and insulin resistance. We have explored the O-GlcNAcylation of mitochondrial proteins from myoblast cells under basal (4mM) and high glucose (30mM) conditions using a combination of proteomic approaches. Furthermore, we have assessed the accompanied changes in the phosphorylation of mitochondrial proteins. We report that a number of mitochondrial proteins are O-GlcNAcylated under basal condition which is altered under high glucose condition. In addition, we report that exposure to high glucose not only changes the O-GlcNAcylation of mitochondrial proteins but also changes their phosphorylation profiles. The dynamic and complex interplay between O-GlcNAcylation and phosphorylation of mitochondrial proteins was further validated by immunoblot analysis of HSP60, prohibitin, and voltage-dependent anion channel 1 as candidate proteins. O-GlcNAcylation of mitochondrial proteins may play a role in normal functioning of mitochondria. High glucose induced changes in O-GlcNAcylation and phosphorylation of mitochondrial proteins may be associated with mitochondrial dysfunction and insulin resistance.
Assuntos
Acetilglucosamina/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , Proteínas Mitocondriais/metabolismo , Mioblastos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular , Camundongos , Mitocôndrias/metabolismo , Mioblastos/citologia , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Post-translational modification of proteins at serine and threonine side chains by ß-N-acetylglucosamine (O-GlcNAc) mediated by the enzyme ß-N-acetylglucosamine transferase has been emerging as a fundamental regulatory mechanism encompassing a wide range of proteins involved in cell division, metabolism, transcription and cell signaling. Furthermore, an extensive interplay between O-GlcNAc modification and serine/threonine phosphorylation in a variety of proteins has been reported to exist. However, our understanding of the regulatory mechanisms involved in O-GlcNAc modification and its interplay with serine/threonine phosphorylation in proteins is still elusive. Recent success in the mapping of O-GlcNAc modification sites in proteins as a result of technological advancement in mass spectrometry have revealed two important clues which may be inherently connected to the regulation of O-GlcNAc modification and its interplay with phosphorylation in proteins. First, almost all O-GlcNAc modified proteins are known phospho proteins. Second, the prevalence of tyrosine phosphorylation among O-GlcNAc modified proteins is exceptionally higher (~68%) than its normal occurrence (~2%) alone. We hypothesize that phosphorylation may be a requisite for O-GlcNAc modification and tyrosine phosphorylation plays a role in the interplay between O-GlcNAc modification and serine/threonine phosphorylation in proteins. In other words, the interplay between O-GlcNAc modification and phosphorylation is not limited to serine/threonine phosphorylation but also includes tyrosine phosphorylation. Our hypothesis provides an opportunity to understand the underlying mechanism involved in O-GlcNAc modification and its interplay with serine/threonine phosphorylation in proteins. Furthermore, implication of our hypothesis extends to tyrosine kinase signaling.
RESUMO
Prohibitin (PHB or PHB1) is an evolutionarily conserved ubiquitously expressed multifunctional protein and is present in various cellular compartments. Phosphorylation of PHB has been suggested as one of the potential mechanisms in the regulation of its various functions however exact sites of phosphorylation remain to be determined. To better understand the functional relevance of phosphorylation of PHB, we have explored the potential sites of phosphorylation using combination of approaches including phosphoamino specific immunoblotting, proteolysis, two-dimensional gel electrophoresis, phosphoamino acid analysis and site-directed mutagenesis techniques and report that tyrosine 114 (Tyr 114) in PHB is phosphorylated in response to insulin stimulation. In addition, using active insulin receptor (IR) and synthetic biotinylated PHB peptide (PHB(107-121)) we have shown that IR also phosphorylates Tyr 114 in an in vitro kinase assay. Phosphorylation of PHB at Tyr 114 was confirmed by immunoblotting using anti-phosphoTyr 114 specific antibody. Furthermore, we demonstrate that SH2 domain containing tyrosine phosphatase-1 (Shp1) co-immunoprecipitate with PHB antiserum after insulin induced phosphorylation of PHB. Biotinylated-PHB(107-121) peptide phosphorylated at Tyr 114 was also able to pull down Shp1 in pull down assays. Non-phosphorylated PHB(107-121) peptide, corresponding PHB2(121-135) peptide and Tyr114Phe mutant-PHB fail to pull down Shp1. In summary, we have identified Tyr 114 in PHB as an important site of phosphorylation and phosphorylation at this residue creates a binding site for Shp1 both in vivo and in vitro.
Assuntos
Insulina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação/genética , Linhagem Celular , Linhagem Celular Tumoral , Primers do DNA/genética , Feminino , Humanos , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Fosforilação , Proibitinas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/genética , Homologia de Sequência de Aminoácidos , Transfecção , Tirosina/químicaRESUMO
The resident immune cells (e.g., macrophages) present in major metabolic tissues, such as adipose and liver tissues, play crucial roles in respective tissue homeostasis through cross talk with metabolic tissues, and consequently in metabolic homeostasis at the systemic level, and their dysregulation contributes to metabolic dysregulation at large, as well as many associated diseases. Moreover, the cross talk between different resident immune cells and metabolic tissues is not limited to an intra-organ level but also includes interorgan cross talk, as they work in a coordinated manner throughout the body, such as in adipose tissue, skeletal muscle, and liver. Thus, it is important to determine the impact of altered immune functions on metabolic homeostasis and vice versa, to enhance our knowledge of immunometabolic biology. Glucose and insulin tolerance tests are simple methods that enable the measurement and analysis of the overall glucose homeostasis at the systemic level. Here we describe the process of performing metabolic tests for glucose homeostasis in mice, as mouse models are often used for defining the mechanistic underpinnings of physiology and pathophysiology related to immunometabolism, and in preclinical studies.
Assuntos
Glucose/metabolismo , Homeostase/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiologia , Animais , Glicemia/metabolismo , Teste de Tolerância a Glucose/métodos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologiaRESUMO
Mitochondrial protein prohibitin (PHB) is known to associate with the plasma membrane of various cell types. However, biological function of plasma membrane associated PHB is not known. Recently we have shown that PHB undergoes tyrosine phosphorylation in response to insulin and here we report that PHB interacts with phosphatidylinositol 3,4,5-triphosphate (PIP3). Furthermore, we demonstrate that over expression of PHB attenuates insulin signaling downstream of phosphatidylinositol 3 (PI3) kinase. This effect was not observed with over expression of tyrosine phosphorylation site mutant-PHB suggesting a role for tyrosine phosphorylation of PHB in this process. Interestingly phosphorylation of PHB by Akt attenuates its interaction with PIP3 and enhances insulin signaling. Thus, phosphorylation of PHB and its interaction with PIP3 may be a part of the regulatory mechanisms that is involved in the modulation of insulin signaling. We speculate that phosphorylation of PHB may serve as a general mechanism in the regulation of PI3 kinase signaling including growth factors and immune receptor signaling.
Assuntos
Insulina/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Células 3T3-L1 , Sequência de Aminoácidos , Animais , Humanos , Camundongos , Dados de Sequência Molecular , Fosforilação , Proibitinas , Proteínas Repressoras/genética , Transdução de Sinais , Tirosina/metabolismoRESUMO
Rapid advances in the cancer stem cell (CSC) field have provided cause for optimism for the development of more reliable cancer therapies in the future. Strategies aimed at efficient targeting of CSCs are becoming important for monitoring the progress of cancer therapy and for evaluating new therapeutic approaches. Here, we characterize and compare the specific markers that have been found to be present on stem cells, cancer cells and CSCs in selected tissues (colon, breast, liver, pancreas and prostate). We then discuss future directions of this intriguing new research field in the context of new diagnostic and therapeutic opportunities.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias/terapia , Células-Tronco Neoplásicas/metabolismo , Humanos , Modelos Biológicos , Neoplasias/metabolismoRESUMO
Virus infection induces different cellular responses in infected cells. These include cellular stress responses like autophagy and unfolded protein response (UPR). Both autophagy and UPR are connected to programed cell death I (apoptosis) in chronic stress conditions to regulate cellular homeostasis via Bcl2 family proteins, CHOP and Beclin-1. In this review article we first briefly discuss arboviruses, influenza virus, and HIV and then describe the concepts of apoptosis, autophagy, and UPR. Finally, we focus upon how apoptosis, autophagy, and UPR are involved in the regulation of cellular responses to arboviruses, influenza virus and HIV infections. Abbreviation: AIDS: Acquired Immunodeficiency Syndrome; ATF6: Activating Transcription Factor 6; ATG6: Autophagy-specific Gene 6; BAG3: BCL Associated Athanogene 3; Bak: BCL-2-Anatagonist/Killer1; Bax; BCL-2: Associated X protein; Bcl-2: B cell Lymphoma 2x; BiP: Chaperon immunoglobulin heavy chain binding Protein; CARD: Caspase Recruitment Domain; cART: combination Antiretroviral Therapy; CCR5: C-C Chemokine Receptor type 5; CD4: Cluster of Differentiation 4; CHOP: C/EBP homologous protein; CXCR4: C-X-C Chemokine Receptor Type 4; Cyto c: Cytochrome C; DCs: Dendritic Cells; EDEM1: ER-degradation enhancing-a-mannosidase-like protein 1; ENV: Envelope; ER: Endoplasmic Reticulum; FasR: Fas Receptor;G2: Gap 2; G2/M: Gap2/Mitosis; GFAP: Glial Fibrillary Acidic Protein; GP120: Glycoprotein120; GP41: Glycoprotein41; HAND: HIV Associated Neurodegenerative Disease; HEK: Human Embryonic Kidney; HeLa: Human Cervical Epithelial Carcinoma; HIV: Human Immunodeficiency Virus; IPS-1: IFN-ß promoter stimulator 1; IRE-1: Inositol Requiring Enzyme 1; IRGM: Immunity Related GTPase Family M protein; LAMP2A: Lysosome Associated Membrane Protein 2A; LC3: Microtubule Associated Light Chain 3; MDA5: Melanoma Differentiation Associated gene 5; MEF: Mouse Embryonic Fibroblast; MMP: Mitochondrial Membrane Permeabilization; Nef: Negative Regulatory Factor; OASIS: Old Astrocyte Specifically Induced Substrate; PAMP: Pathogen-Associated Molecular Pattern; PERK: Pancreatic Endoplasmic Reticulum Kinase; PRR: Pattern Recognition Receptor; Puma: P53 Upregulated Modulator of Apoptosis; RIG-I: Retinoic acid-Inducible Gene-I; Tat: Transactivator Protein of HIV; TLR: Toll-like receptor; ULK1: Unc51 Like Autophagy Activating Kinase 1; UPR: Unfolded Protein Response; Vpr: Viral Protein Regulatory; XBP1: X-Box Binding Protein 1.
Assuntos
Apoptose , Arbovírus/metabolismo , Autofagia , HIV/metabolismo , Interações entre Hospedeiro e Microrganismos , Orthomyxoviridae/metabolismo , Resposta a Proteínas não Dobradas , Animais , Proteínas Reguladoras de Apoptose , Arbovírus/genética , HIV/genética , Humanos , Camundongos , Orthomyxoviridae/genética , Transdução de Sinais , Estresse FisiológicoRESUMO
Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Humanos , Modelos Biológicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Temozolomida/farmacologia , Temozolomida/uso terapêuticoRESUMO
Cardiovascular disease leading to heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Improved pharmacological and interventional coronary procedures have led to improved outcomes following acute myocardial infarction. This success has translated into an unforeseen increased incidence in HF. This review summarizes the signaling pathways implicated in the transition to HF following cardiac injury. In addition, we provide an update on cell death signaling and discuss recent advances in cardiac fibrosis as an independent event leading to HF. Finally, we discuss cell-based therapies and their possible use to avert the deteriorating nature of HF. © 2019 American Physiological Society. Compr Physiol 9:75-125, 2019.
Assuntos
Insuficiência Cardíaca/metabolismo , Medicina Regenerativa/métodos , Transdução de Sinais , Engenharia Tecidual/métodos , Animais , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Humanos , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
The cholesterol biosynthesis pathway, also referred to as the mevalonate (MVA) pathway, is responsible for the biosynthesis of two key isoprenoids: farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational modification of small GTPases by FPP and GGPP has captured much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) catalyzes the conversion of HMG-CoA to MVA, and is the rate-limiting step in the biosynthesis of cholesterol. Statins are HMGCR inhibitors that are used extensively in the treatment of hypercholesterolemia. Inhibitors of the MVA pathway exhibit anti-tumor effects and may reduce cancer incidence and cancer-related mortality in humans. In this review, we will focus on the mevalonate cascade and its regulation in cholesterol metabolism as well as polymorphisms of the MVA cascade in cancer development, infectious and cardiovascular disease (CVD).
Assuntos
Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Infecções/metabolismo , Ácido Mevalônico/metabolismo , Neoplasias/metabolismo , Acil Coenzima A/metabolismo , Animais , Colesterol/biossíntese , GTP Fosfo-Hidrolases/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Sesquiterpenos/metabolismo , Transdução de SinaisRESUMO
Sex differences are known to exist in adipose and immune functions in the body, and sex steroid hormones are known to be involved in sexually dimorphic biological and pathological processes related to adipose-immune interaction. However, our knowledge of proteins that mediate such differences is poor. Two novel obese mice models, Mito-Ob and m-Mito-Ob, that have been reported recently have revealed an unexpected role of a pleiotropic protein, prohibitin (PHB), in sex differences in adipose and immune functions. This discovery points towards a role of pleiotropic proteins and their potential interplay with sex steroid hormones in mediating sexually dimorphic adipose-immune interaction.
RESUMO
Obesity increases the risk for nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. However, the underlying mechanisms involved in the disease process remain unclear. Recently, we have developed a transgenic obese mouse model (Mito-Ob) by prohibitin mediated mitochondrial remodeling in adipocytes. The Mito-Ob mice develop obesity in a sex-neutral manner, but obesity-associated adipose inflammation and metabolic dysregulation in a male sex-specific manner. Here we report that with aging, the male Mito-Ob mice spontaneously develop obesity-linked NASH and hepatocellular carcinoma (HCC). In contrast, the female Mito-Ob mice maintained normal glucose and insulin levels and did not develop NASH and HCC. The anti-inflammatory peptide ghrelin was significantly upregulated in the female mice and down regulated in the male mice compared with respective control mice. In addition, a reduction in the markers of mitochondrial content and function was found in the liver of male Mito-Ob mice with NASH/HCC development. We found that ERK1/2 signaling was significantly upregulated whereas STAT3 signaling was significantly down regulated in the tumors from Mito-Ob mice. These data provide a proof-of-concept that the metabolic and inflammatory status of the adipose tissue and their interplay at the systemic and hepatic level play a central role in the pathogenesis of obesity-linked NASH and HCC.
Assuntos
Carcinoma Hepatocelular/etiologia , Resistência à Insulina , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/imunologia , Proteínas Repressoras/deficiência , Animais , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Proibitinas , Fator de Transcrição STAT3/metabolismo , Caracteres SexuaisRESUMO
Prohibitin (PHB) was discovered in a quest to find genes with antiproliferative functions. However, the attribute of PHB that is responsible for its antiproliferative function remains elusive. Meanwhile, recent studies have established PHB as a pleiotropic protein with roles in metabolism, immunity, and senescence. PHB has cell compartment-specific functions, acting as a scaffolding protein in mitochondria, an adaptor molecule in membrane signaling, and a transcriptional coregulator in the nucleus. However, it remains unclear whether different functions and locations of PHB are interrelated or independent from each other, or if PHB works in a tissue-specific manner. Here, we discuss new findings on the role of PHB in adipose-immune interaction and an unexpected role in sex differences in adipose and immune functions.
Assuntos
Adiposidade/fisiologia , Obesidade/metabolismo , Proteínas Repressoras/metabolismo , Adiposidade/genética , Animais , Núcleo Celular/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/genética , Obesidade/imunologia , Proibitinas , Proteínas Repressoras/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologiaRESUMO
Mitochondria play vital roles in the maintenance of cellular homeostasis. They are a storehouse of cellular energy and antioxidative enzymes. Because of its immense role and function in the development of an organism, this organelle is required for the survival. Defects in mitochondrial proteins lead to complex mitochondrial disorders and heterogeneous diseases such as cancer, type 2 diabetes, and cardiovascular and neurodegenerative diseases. It is widely known in the literature that some of the mitochondrial proteins are regulated by posttranslational modifications. Hence, designing methods to assess these modifications in mitochondria will be an important way to study the regulatory roles of mitochondrial proteins in greater detail. In this chapter, we outlined procedures to isolate mitochondria from cells and separate the mitochondrial proteins by two-dimensional gel electrophoresis and identify the different posttranslational modifications in them by using antibodies specific to each posttranslational modification.
Assuntos
Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Fracionamento Celular , Linhagem Celular , Humanos , Camundongos , Proteômica/métodosRESUMO
Adipocytes are the primary cells in the body that store excess energy as triglycerides. To perform this specialized function, adipocytes rely on their mitochondria; however, the role of adipocyte mitochondria in the regulation of adipose tissue homeostasis and its impact on metabolic regulation is not understood. We developed a transgenic mouse model, Mito-Ob, overexpressing prohibitin (PHB) in adipocytes. Mito-Ob mice developed obesity due to upregulation of mitochondrial biogenesis in adipocytes. Of note, Mito-Ob female mice developed more visceral fat than male mice. However, female mice exhibited no change in glucose homeostasis and had normal insulin and high adiponectin levels, whereas male mice had impaired glucose homeostasis, compromised brown adipose tissue structure, and high insulin and low adiponectin levels. Mechanistically, we found that PHB overexpression enhances the cross talk between the mitochondria and the nucleus and facilitates mitochondrial biogenesis. The data suggest a critical role of PHB and adipocyte mitochondria in adipose tissue homeostasis and reveal sex differences in the effect of PHB-induced adipocyte mitochondrial remodeling on whole-body metabolism. Targeting adipocyte mitochondria may provide new therapeutic opportunities for the treatment of obesity, a major risk factor for type 2 diabetes.