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1.
JCI Insight ; 6(17)2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34494556

RESUMO

Lipin 1 regulates cellular lipid homeostasis through roles in glycerolipid synthesis (through phosphatidic acid phosphatase activity) and transcriptional coactivation. Lipin 1-deficient individuals exhibit episodic disease symptoms that are triggered by metabolic stress, such as stress caused by prolonged fasting. We sought to identify critical lipin 1 activities during fasting. We determined that lipin 1 deficiency induces widespread alternative mRNA splicing in liver during fasting, much of which is normalized by refeeding. The role of lipin 1 in mRNA splicing was largely independent of its enzymatic function. We identified interactions between lipin 1 and spliceosome proteins, as well as a requirement for lipin 1 to maintain homeostatic levels of spliceosome small nuclear RNAs and specific RNA splicing factors. In fasted Lpin1-/- liver, we identified a correspondence between alternative splicing of phospholipid biosynthetic enzymes and dysregulated phospholipid levels; splicing patterns and phospholipid levels were partly normalized by feeding. Thus, lipin 1 influences hepatic lipid metabolism through mRNA splicing, as well as through enzymatic and transcriptional activities, and fasting exacerbates the deleterious effects of lipin 1 deficiency on metabolic homeostasis.

2.
Nat Commun ; 12(1): 4718, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354069

RESUMO

Phospholipid synthesis and fat storage as triglycerides are regulated by lipin phosphatidic acid phosphatases (PAPs), whose enzymatic PAP function requires association with cellular membranes. Using hydrogen deuterium exchange mass spectrometry, we find mouse lipin 1 binds membranes through an N-terminal amphipathic helix, the Ig-like domain and HAD phosphatase catalytic core, and a middle lipin (M-Lip) domain that is conserved in mammalian and mammalian-like lipins. Crystal structures of the M-Lip domain reveal a previously unrecognized protein fold that dimerizes. The isolated M-Lip domain binds membranes both in vitro and in cells through conserved basic and hydrophobic residues. Deletion of the M-Lip domain in lipin 1 reduces PAP activity, membrane association, and oligomerization, alters subcellular localization, diminishes acceleration of adipocyte differentiation, but does not affect transcriptional co-activation. This establishes the M-Lip domain as a dimeric protein fold that binds membranes and is critical for full functionality of mammalian lipins.


Assuntos
Fosfatidato Fosfatase/química , Células 3T3-L1 , Adipogenia , Sequência de Aminoácidos , Animais , Membrana Celular/metabolismo , Sequência Conservada , Cristalografia por Raios X , Células HEK293 , Humanos , Espectrometria de Massa com Troca Hidrogênio-Deutério , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Fosfatidato Fosfatase/genética , Fosfatidato Fosfatase/metabolismo , Ligação Proteica , Domínios Proteicos , Dobramento de Proteína , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Transcrição Genética
3.
Nat Metab ; 3(7): 940-953, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34282353

RESUMO

Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N6-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.


Assuntos
Adenosina/análogos & derivados , Metabolismo Energético , Regulação da Expressão Gênica , Característica Quantitativa Herdável , Transcrição Genética , Adenosina/metabolismo , Animais , Feminino , Metabolismo dos Lipídeos , Masculino , Metilação , Camundongos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT5/metabolismo , Fatores Sexuais , Transdução de Sinais
4.
Pharmacol Rev ; 73(2): 730-762, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33653873

RESUMO

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs.

5.
Nature ; 590(7846): 480-485, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33597756

RESUMO

Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle4-to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.


Assuntos
Tecido Adiposo/metabolismo , Creatina Quinase Forma BB/metabolismo , Creatina/metabolismo , Termogênese , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/enzimologia , Animais , Creatina Quinase Forma BB/deficiência , Creatina Quinase Forma BB/genética , AMP Cíclico/metabolismo , Metabolismo Energético/genética , Feminino , Glucose/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Obesidade/enzimologia , Obesidade/genética , Obesidade/metabolismo , Transdução de Sinais
6.
Mol Syst Biol ; 17(1): e9684, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417276

RESUMO

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/genética , Glucose/efeitos adversos , Resistência à Insulina/genética , MAP Quinase Quinase 6/genética , Proteínas Nucleares/genética , Animais , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Lipidômica , Masculino , Camundongos , Fosfatidilcolinas/metabolismo , Triglicerídeos/metabolismo
7.
Sci Transl Med ; 12(555)2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32759275

RESUMO

Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue ESR1/Esr1 expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ERα in fat, we selectively deleted Esr1 from white and brown adipocytes in mice. In white adipose tissue, Esr1 controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, Esr1 was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of Esr1 deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit Polg1 We identified Polg1 as an ERα target gene by showing that ERα binds the Polg1 promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.


Assuntos
Adipócitos Marrons , Receptor alfa de Estrogênio , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Termogênese , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
8.
J Biol Chem ; 295(44): 15054-15069, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-32855239

RESUMO

Strategies to increase energy expenditure are an attractive approach to reduce excess fat storage and body weight to improve metabolic health. In mammals, uncoupling protein-1 (UCP1) in brown and beige adipocytes uncouples fatty acid oxidation from ATP generation in mitochondria and promotes energy dissipation as heat. We set out to identify small molecules that enhance UCP1 levels and activity using a high-throughput screen of nearly 12,000 compounds in mouse brown adipocytes. We identified a family of compounds that increase Ucp1 expression and mitochondrial activity (including un-coupled respiration) in mouse brown adipocytes and human brown and white adipocytes. The mechanism of action may be through compound binding to A kinase anchoring protein (AKAP) 1, modulating its localization to mitochondria and its interaction with protein kinase A (PKA), a known node in the ß-adrenergic signaling pathway. In mice, the hit compound increased body temperature, UCP1 protein levels, and thermogenic gene expression. Some of the compound effects on mitochondrial function were UCP1- or AKAP1-independent, suggesting compound effects on multiple nodes of energy regulation. Overall, our results highlight a role for AKAP1 in thermogenesis, uncoupled respiration, and regulation energy balance.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese , Adipócitos Marrons/enzimologia , Adipócitos Marrons/metabolismo , Adipócitos Brancos/enzimologia , Adipócitos Brancos/metabolismo , Animais , Células Cultivadas , Metabolismo Energético , Ativação Enzimática , Perfilação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais
9.
J Clin Invest ; 130(11): 5688-5702, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32701509

RESUMO

Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.


Assuntos
Adipócitos/enzimologia , Adiposidade , Dosagem de Genes , Regulação Enzimológica da Expressão Gênica , Histona Desmetilases , Caracteres Sexuais , Cromossomo X , Animais , Montagem e Desmontagem da Cromatina , Feminino , Histona Desmetilases/biossíntese , Histona Desmetilases/genética , Humanos , Masculino , Camundongos , Camundongos Mutantes , Cromossomo X/genética , Cromossomo X/metabolismo
10.
EMBO J ; 39(13): e104073, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432379

RESUMO

Respirometry is the gold standard measurement of mitochondrial oxidative function, as it reflects the activity of the electron transport chain complexes working together. However, the requirement for freshly isolated mitochondria hinders the feasibility of respirometry in multi-site clinical studies and retrospective studies. Here, we describe a novel respirometry approach suited for frozen samples by restoring electron transfer components lost during freeze/thaw and correcting for variable permeabilization of mitochondrial membranes. This approach preserves 90-95% of the maximal respiratory capacity in frozen samples and can be applied to isolated mitochondria, permeabilized cells, and tissue homogenates with high sensitivity. We find that primary changes in mitochondrial function, detected in fresh tissue, are preserved in frozen samples years after collection. This approach will enable analysis of the integrated function of mitochondrial Complexes I to IV in one measurement, collected at remote sites or retrospectively in samples residing in tissue biobanks.


Assuntos
Criopreservação , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/metabolismo , Consumo de Oxigênio , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Masculino , Camundongos
11.
Nat Commun ; 11(1): 1734, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242008

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

12.
Nat Commun ; 11(1): 1309, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161260

RESUMO

Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and C-Lip regions that are separated by 500-residues in humans. To understand how the N-Lip and C-Lip combine for PAP function, we determined crystal structures of Tetrahymena thermophila Pah2 (Tt Pah2) that directly fuses the N-Lip and C-Lip. Tt Pah2 adopts a two-domain architecture where the N-Lip combines with part of the C-Lip to form an immunoglobulin-like domain and the remaining C-Lip forms a HAD-like catalytic domain. An N-Lip C-Lip fusion of mouse lipin-2 is catalytically active, which suggests mammalian lipins function with the same domain architecture as Tt Pah2. HDX-MS identifies an N-terminal amphipathic helix essential for membrane association. Disease-mutations disrupt catalysis or destabilize the protein fold. This illustrates mechanisms for lipin/Pah PAP function, membrane association, and lipin-related pathologies.


Assuntos
Fosfatidato Fosfatase/metabolismo , Fosfatidato Fosfatase/ultraestrutura , Proteínas de Protozoários/ultraestrutura , Domínio Catalítico/genética , Cristalografia por Raios X , Células HEK293 , Humanos , Fosfatidato Fosfatase/genética , Fosfatidato Fosfatase/isolamento & purificação , Conformação Proteica em alfa-Hélice , Proteínas de Protozoários/genética , Proteínas de Protozoários/isolamento & purificação , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/ultraestrutura , Tetrahymena thermophila/enzimologia , Transfecção
13.
J Lipid Res ; 61(3): 413-421, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31941672

RESUMO

Zinc metallopeptidase STE24 (ZMPSTE24) is essential for the conversion of farnesyl-prelamin A to mature lamin A, a key component of the nuclear lamina. In the absence of ZMPSTE24, farnesyl-prelamin A accumulates in the nucleus and exerts toxicity, causing a variety of disease phenotypes. By ∼4 months of age, both male and female Zmpste24 -/- mice manifest a near-complete loss of adipose tissue, but it has never been clear whether this phenotype is a direct consequence of farnesyl-prelamin A toxicity in adipocytes. To address this question, we generated a conditional knockout Zmpste24 allele and used it to create adipocyte-specific Zmpste24-knockout mice. To boost farnesyl-prelamin A levels, we bred in the "prelamin A-only" Lmna allele. Gene expression, immunoblotting, and immunohistochemistry experiments revealed that adipose tissue in these mice had decreased Zmpste24 expression along with strikingly increased accumulation of prelamin A. In male mice, Zmpste24 deficiency in adipocytes was accompanied by modest changes in adipose stores (an 11% decrease in body weight, a 23% decrease in body fat mass, and significantly smaller gonadal and inguinal white adipose depots). No changes in adipose stores were detected in female mice, likely because prelamin A expression in adipose tissue is lower in female mice. Zmpste24 deficiency in adipocytes did not alter the number of macrophages in adipose tissue, nor did it alter plasma levels of glucose, triglycerides, or fatty acids. We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl-prelamin A, reduces adipose tissue stores, but only modestly and only in male mice.


Assuntos
Tecido Adiposo/metabolismo , Lamina Tipo A/metabolismo , Proteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Tecido Adiposo/química , Alelos , Animais , Núcleo Celular/química , Núcleo Celular/metabolismo , Feminino , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Metaloendopeptidases/deficiência , Metaloendopeptidases/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos
14.
Mol Metab ; 30: 30-47, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31767179

RESUMO

OBJECTIVE: Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and has also been associated with several cardiometabolic traits in both mouse and human studies. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males. METHODS: Using adeno-associated viral vectors we expressed LCN2 in either adipose or liver in a tissue specific manner on the background of a whole-body Lcn2 knockout or wildtype mice. Metabolic phenotypes including body weight, body composition, plasma and liver lipids, glucose homeostasis, insulin resistance, mitochondrial phenotyping, and metabolic cage studies were monitored. RESULTS: We studied the genetics of LCN2 expression and associated clinical traits in both males and females in a panel of 100 inbred strains of mice (HMDP). The natural variation in Lcn2 expression across the HMDP exhibits high heritability, and genetic mapping suggests that it is regulated in part by Lipin1 gene variation. The correlation analyses revealed striking tissue dependent sex differences in obesity, insulin resistance, hepatic steatosis, and dyslipidemia. To understand the causal relationships, we examined the effects of expression of LCN2 selectively in liver or adipose. On a Lcn2-null background, LCN2 expression in white adipose promoted metabolic disturbances in females but not males. It acted in an autocrine/paracrine manner, resulting in mitochondrial dysfunction and an upregulation of inflammatory and fibrotic genes. On the other hand, on a null background, expression of LCN2 in liver had no discernible impact on the traits examined despite increasing the levels of circulating LCN2 more than adipose LCN2 expression. The mechanisms underlying the sex-specific action of LCN2 are unclear, but our results indicate that adipose LCN2 negatively regulates its receptor, LRP2 (or megalin), and its repressor, ERα, in a female-specific manner and that the effects of LCN2 on metabolic traits are mediated in part by LRP2. CONCLUSIONS: Following up on our population-based studies, we demonstrate that LCN2 acts in a highly sex- and tissue-specific manner in mice. Our results have important implications for human studies, emphasizing the importance of sex and the tissue source of LCN2.


Assuntos
Tecido Adiposo/metabolismo , Lipocalina-2/metabolismo , Adiposidade , Animais , Composição Corporal , Peso Corporal , Feminino , Glucose/análise , Homeostase , Resistência à Insulina , Lipídeos/análise , Lipocalina-2/genética , Lipocalina-2/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Obesidade/metabolismo , Fatores Sexuais
15.
Elife ; 82019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31644425

RESUMO

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.


Assuntos
Adipócitos/efeitos dos fármacos , Comunicação Celular , Regulação da Expressão Gênica , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Interleucina-10/metabolismo , Linfócitos/metabolismo , Termogênese , Adipócitos/fisiologia , Animais , Camundongos , Análise de Célula Única , Transcrição Genética
16.
Arterioscler Thromb Vasc Biol ; 39(9): 1776-1786, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31340670

RESUMO

OBJECTIVE: Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and ß-oxidation. CONCLUSIONS: DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.


Assuntos
Fígado Gorduroso/induzido quimicamente , Hiperlipidemias/induzido quimicamente , Mitocôndrias/metabolismo , Emissões de Veículos/toxicidade , Animais , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Triglicerídeos/metabolismo
17.
Cell Rep ; 27(12): 3413-3421.e3, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216464

RESUMO

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.


Assuntos
Alopecia/tratamento farmacológico , Autofagia/efeitos dos fármacos , Folículo Piloso/efeitos dos fármacos , Cabelo/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Compostos Alílicos/farmacologia , Alopecia/genética , Alopecia/metabolismo , Animais , Autofagia/genética , Butiratos/farmacologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Feminino , Cabelo/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Ácidos Cetoglutáricos/farmacologia , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Oligomicinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética
18.
Nat Commun ; 10(1): 2631, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201301

RESUMO

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/metabolismo , Aterosclerose/genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Cromossomo X/fisiologia , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Fatores Sexuais , Proteína da Região Y Determinante do Sexo/genética , Testículo/metabolismo
19.
Mol Metab ; 25: 50-63, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31027994

RESUMO

OBJECTIVE: Obesity has increased to pandemic levels and enhanced understanding of adipose regulation is required for new treatment strategies. Although bone morphogenetic proteins (BMPs) influence adipogenesis, the effect of BMP antagonists such as Noggin is largely unknown. The aim of the study was to define the role of Noggin, an extracellular BMP inhibitor, in adipogenesis. METHODS: We generated adipose-derived progenitor cells and a mouse model with adipocyte-specific Noggin deletion using the AdiponectinCre transgenic mouse, and determined the adipose phenotype of Noggin-deficiency. RESULTS: Our studies showed that Noggin is expressed in progenitor cells but declines in adipocytes, possibly allowing for lipid accumulation. Correspondingly, adipocyte-specific Noggin deletion in vivo promoted age-related obesity in both genders with no change in food intake. Although the loss of Noggin caused white adipose tissue hypertrophy, and whitening and impaired function in brown adipose tissue in both genders, there were clear gender differences with the females being most affected. The females had suppressed expression of brown adipose markers and thermogenic genes including peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1alpha) and uncoupling protein 1 (UCP1) as well as genes associated with adipogenesis and lipid metabolism. The males, on the other hand, had early changes in a few BAT markers and thermogenic genes, but the main changes were in the genes associated with adipogenesis and lipid metabolism. Further characterization revealed that both genders had reductions in VO2, VCO2, and RER, whereas females also had reduced heat production. Noggin was also reduced in diet-induced obesity in inbred mice consistent with the obesity phenotype of the Noggin-deficient mice. CONCLUSIONS: BMP signaling regulates female and male adipogenesis through different metabolic pathways. Modulation of adipose tissue metabolism by select BMP antagonists may be a strategy for long-term regulation of age-related weight gain and obesity.


Assuntos
Adipócitos/metabolismo , Adipogenia/fisiologia , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Transporte/metabolismo , Obesidade/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/efeitos dos fármacos , Proteínas de Transporte/genética , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Estudos de Associação Genética , Produto da Acumulação Lipídica , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais/genética , Termogênese/genética , Termogênese/fisiologia , Transcriptoma , Proteína Desacopladora 1/genética
20.
J Lipid Res ; 60(4): 728-733, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30804008

RESUMO

The regulation of cellular lipid storage and membrane lipid composition plays a critical role in metabolic homeostasis, and dysregulation may contribute to disorders such as obesity, fatty liver, type 2 diabetes, and cardiovascular disease. The mammalian lipin proteins (lipin 1, lipin 2, and lipin 3) are phosphatidic acid phosphatase (PAP) enzymes that modulate levels of cellular triacylglycerols and phospholipids, and also regulate lipid intermediates in cellular signaling pathways. Lipin proteins also have the ability to coactivate/corepress transcription. In humans and mice, lipin gene mutations cause severe metabolic phenotypes including rhabdomyolysis (lipin 1), autoinflammatory disease (lipin 2), and impaired intestinal lipoprotein assembly (lipin 2/lipin 3). Characterization of these diseases has revealed roles for lipin PAP activity in fundamental cellular processes such as autophagy, inflammasome activation, and lipoprotein assembly. Lipin protein activity is regulated at pre- and posttranscriptional levels, which suggests a need for their ordered response to specific physiological stimuli. Challenges for the future include better elucidation of the unique biochemical and physiological properties of individual lipin family members and determination of lipin protein structure-function relationships. Further research may propel exploration of lipin proteins as viable therapeutic targets in metabolic or inflammatory disorders.


Assuntos
Inflamação/metabolismo , Lipídeos/biossíntese , Síndrome Metabólica/metabolismo , Fosfatidato Fosfatase/metabolismo , Animais , Autofagia , Humanos , Inflamação/patologia , Síndrome Metabólica/patologia , Compostos Orgânicos/metabolismo
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