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1.
J Mol Model ; 30(6): 170, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38753123

RESUMO

CONTEXT: In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. METHODS: We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.


Assuntos
Reposicionamento de Medicamentos , Imidazóis , Indóis , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor para Produtos Finais de Glicação Avançada , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/química , Humanos , Indóis/química , Indóis/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Ligação Proteica , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Sítios de Ligação
2.
Rev Invest Clin ; 76(2): 65-79, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38718804

RESUMO

UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).


Assuntos
Tecido Adiposo , Inflamação , Doenças Metabólicas , Obesidade , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Obesidade/imunologia , Obesidade/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia , Metabolismo Energético/fisiologia , Adipócitos/metabolismo , Adipócitos/imunologia , Metabolismo dos Lipídeos/fisiologia , Animais , Homeostase
3.
J Nanobiotechnology ; 22(1): 226, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38711066

RESUMO

Nanozyme, characterized by outstanding and inherent enzyme-mimicking properties, have emerged as highly promising alternatives to natural enzymes owning to their exceptional attributes such as regulation of oxidative stress, convenient storage, adjustable catalytic activities, remarkable stability, and effortless scalability for large-scale production. Given the potent regulatory function of nanozymes on oxidative stress and coupled with the fact that reactive oxygen species (ROS) play a vital role in the occurrence and exacerbation of metabolic diseases, nanozyme offer a unique perspective for therapy through multifunctional activities, achieving essential results in the treatment of metabolic diseases by directly scavenging excess ROS or regulating pathologically related molecules. The rational design strategies, nanozyme-enabled therapeutic mechanisms at the cellular level, and the therapies of nanozyme for several typical metabolic diseases and underlying mechanisms are discussed, mainly including obesity, diabetes, cardiovascular disease, diabetic wound healing, and others. Finally, the pharmacokinetics, safety analysis, challenges, and outlooks for the application of nanozyme are also presented. This review will provide some instructive perspectives on nanozyme and promote the development of enzyme-mimicking strategies in metabolic disease therapy.


Assuntos
Doenças Metabólicas , Estresse Oxidativo , Espécies Reativas de Oxigênio , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Animais , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Nanopartículas/química , Enzimas/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Obesidade/metabolismo , Obesidade/tratamento farmacológico
4.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732118

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.


Assuntos
Fígado Gorduroso , Receptores de Calcitriol , Deficiência de Vitamina D , Vitamina D , Humanos , Vitamina D/metabolismo , Animais , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/metabolismo , Receptores de Calcitriol/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/etiologia , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia
5.
Front Endocrinol (Lausanne) ; 15: 1328139, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742195

RESUMO

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.


Assuntos
Doenças Cardiovasculares , Ritmo Circadiano , Doenças Metabólicas , Humanos , Ritmo Circadiano/fisiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Metabólicas/fisiopatologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Transtornos Cronobiológicos/fisiopatologia , Transtornos Cronobiológicos/complicações
6.
Front Endocrinol (Lausanne) ; 15: 1379228, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745956

RESUMO

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.


Assuntos
Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1 , Resistência à Insulina , Lipodistrofia , Liraglutida , Camundongos Knockout , Animais , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Lipodistrofia/tratamento farmacológico , Lipodistrofia/metabolismo , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Glicemia/metabolismo , Insulina/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Camundongos Endogâmicos C57BL
7.
J Agric Food Chem ; 72(15): 8632-8649, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38577880

RESUMO

Our previous studies found that Sea Buckthorn polyphenols (SBP) extract inhibits fatty acid synthase (FAS) in vitro. Thus, we continued to explore possible effects and underlying mechanisms of SBP on complicated metabolic disorders in long-term high-fat-diet (HFD)-fed mice. To reveal that, an integrated approach was developed in this study. Targeted quantitative lipidomics with a total of 904 unique lipids mapping contributes to profiling the comprehensive features of disarranged hepatic lipid homeostasis and discovering a set of newfound lipid-based biomarkers to predict the occurrence and indicate the progression of metabolic disorders beyond current indicators. On the other hand, technologies of intermolecular interactions characterization, especially surface plasmon resonance (SPR) assay, contribute to recognizing targeted bioactive constituents present in SBP. Our findings highlight hepatic lipid homeostasis maintenance and constituent-FAS enzyme interactions, to provide new insights that SBP as a functional food alleviates HFD-induced metabolic disorders in mice via reprograming hepatic lipid homeostasis caused by targeting FAS, owing to four polyphenols directly interacting with FAS and cinaroside binding to FAS with good affinity.


Assuntos
Hippophae , Doenças Metabólicas , Camundongos , Animais , Polifenóis/metabolismo , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Lipídeos/farmacologia , Doenças Metabólicas/metabolismo , Homeostase , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos
8.
Circ Res ; 134(9): 1083-1097, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38662860

RESUMO

Poor air quality accounts for more than 9 million deaths a year globally according to recent estimates. A large portion of these deaths are attributable to cardiovascular causes, with evidence indicating that air pollution may also play an important role in the genesis of key cardiometabolic risk factors. Air pollution is not experienced in isolation but is part of a complex system, influenced by a host of other external environmental exposures, and interacting with intrinsic biologic factors and susceptibility to ultimately determine cardiovascular and metabolic outcomes. Given that the same fossil fuel emission sources that cause climate change also result in air pollution, there is a need for robust approaches that can not only limit climate change but also eliminate air pollution health effects, with an emphasis of protecting the most susceptible but also targeting interventions at the most vulnerable populations. In this review, we summarize the current state of epidemiologic and mechanistic evidence underpinning the association of air pollution with cardiometabolic disease and how complex interactions with other exposures and individual characteristics may modify these associations. We identify gaps in the current literature and suggest emerging approaches for policy makers to holistically approach cardiometabolic health risk and impact assessment.


Assuntos
Poluição do Ar , Doenças Cardiovasculares , Exposição Ambiental , Humanos , Poluição do Ar/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Exposição Ambiental/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Fatores de Risco Cardiometabólico , Expossoma , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia , Material Particulado/efeitos adversos
9.
Nat Metab ; 6(4): 639-650, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38671149

RESUMO

Thyroid hormones (THs) are key hormones that regulate development and metabolism in mammals. In man, the major target tissues for TH action are the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action have been associated with genetic and endocrine diseases in man. Over the past few years, there has been renewed interest in TH action and the therapeutic potential of THs and thyromimetics to treat several metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. Recent advances in the development of tissue and TH receptor isoform-targeted thyromimetics have kindled new hope for translating our fundamental understanding of TH action into an effective therapy. This review provides a concise overview of the historical development of our understanding of TH action, its physiological and pathophysiological effects on metabolism, and future therapeutic applications to treat metabolic dysfunction.


Assuntos
Hormônios Tireóideos , Humanos , Hormônios Tireóideos/metabolismo , Animais , Doenças Metabólicas/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo
10.
Arterioscler Thromb Vasc Biol ; 44(5): 1021-1030, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38572647

RESUMO

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.


Assuntos
Angiotensinogênio , Doenças Cardiovasculares , Doenças Metabólicas , Animais , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/genética , Angiotensinogênio/metabolismo , Angiotensinogênio/genética , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Terapia de Alvo Molecular
11.
Obes Rev ; 25(6): e13740, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38571458

RESUMO

Exosomes are extracellular vesicles, measuring 40-160 nm in diameter, that are released by many cell types and tissues, including adipose tissue. Exosomes are critical mediators of intercellular communication and their contents are complex and diverse. In recent years, accumulating evidence has proved that multiple adipose tissue-derived exosomal noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play pivotal roles in the pathogenesis of diverse metabolic diseases, such as obesity. In this narrative review, we focus on the adipose tissue-derived exosomal ncRNAs, especially exosomal miRNAs, and their dysregulation in multiple types of metabolic diseases. A deeper understanding of the role of adipose tissue-derived exosomal ncRNAs may help provide new diagnostic and treatment methods for metabolic diseases.


Assuntos
Tecido Adiposo , Exossomos , Doenças Metabólicas , RNA não Traduzido , Humanos , Exossomos/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Tecido Adiposo/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/fisiologia , Animais
12.
Metabolism ; 155: 155911, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38609037

RESUMO

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing year by year and has become one of the leading causes of end-stage liver disease worldwide. Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) has been confirmed to play an essential role in the progression of MASLD, but its specific mechanism still needs to be clarified. This study aims to explore the role and mechanism of Trem2 in MASLD. METHODS: Human liver tissues were obtained from patients with MASLD and controls. Myeloid-specific knockout mice (Trem2mKO) and myeloid-specific overexpression mice (Trem2TdT) were fed a high-fat diet, either AMLN or CDAHFD, to establish the MASLD model. Relevant signaling molecules were assessed through lipidomics and RNA-seq analyses after that. RESULTS: Trem2 is upregulated in human MASLD/MASH-associated macrophages and is associated with hepatic steatosis and inflammation progression. Hepatic steatosis and inflammatory responses are exacerbated with the knockout of myeloid Trem2 in MASLD mice, while mice overexpressing Trem2 exhibit the opposite phenomenon. Mechanistically, Trem2mKO can aggravate macrophage pyroptosis through the PI3K/AKT signaling pathway and amplify the resulting inflammatory response. At the same time, Trem2 promotes the inflammation resolution phenotype transformation of macrophages through TGFß1, thereby promoting tissue repair. CONCLUSIONS: Myeloid Trem2 ameliorates the progression of Metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution. We believe targeting myeloid Trem2 could represent a potential avenue for treating MASLD.


Assuntos
Progressão da Doença , Fígado Gorduroso , Inflamação , Macrófagos , Glicoproteínas de Membrana , Camundongos Knockout , Piroptose , Receptores Imunológicos , Animais , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Humanos , Macrófagos/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Piroptose/fisiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/genética , Masculino , Camundongos Endogâmicos C57BL , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Doenças Metabólicas/genética , Fígado/metabolismo , Fígado/patologia
13.
Biomolecules ; 14(4)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38672429

RESUMO

In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.


Assuntos
Produtos Finais de Glicação Avançada , Inflamação , Receptor para Produtos Finais de Glicação Avançada , Humanos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Inflamação/metabolismo , Transdução de Sinais , Neoplasias/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Metabólicas/metabolismo , Doenças Autoimunes/metabolismo
14.
Cell Metab ; 36(5): 912-926, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38608696

RESUMO

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading etiology of chronic liver disease worldwide, with increasing incidence and prevalence in the setting of the obesity epidemic. MASH is also a leading indication for liver transplantation, given its associated risk of progression to end-stage liver disease. A key challenge in managing MASH is the lack of approved pharmacotherapy. In its absence, lifestyle interventions with a focus on healthy nutrition and regular physical activity have been the cornerstone of therapy. Real-world efficacy and sustainability of lifestyle interventions are low, however. Pharmacotherapy development for MASH is emerging with promising data from several agents with different mechanisms of action (MOAs) in phase 3 clinical trials. In this review, we highlight ongoing challenges and potential solutions in drug development for MASH and provide an overview of available data from emerging therapies across multiple MOAs.


Assuntos
Fígado Gorduroso , Humanos , Fígado Gorduroso/terapia , Fígado Gorduroso/metabolismo , Animais , Doenças Metabólicas/metabolismo , Doenças Metabólicas/terapia
15.
Cell Metab ; 36(5): 893-911, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38614092

RESUMO

On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty.


Assuntos
Envelhecimento , Fragilidade , Humanos , Fragilidade/metabolismo , Animais , Envelhecimento/metabolismo , Doenças Metabólicas/metabolismo , Idoso , Metabolismo Energético , Idoso Fragilizado
16.
Am J Physiol Endocrinol Metab ; 326(6): E776-E790, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38568153

RESUMO

Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified in many metabolic functions, including the regulation of hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus, we investigated the function of SMEK1 in white adipose tissue and glucose uptake. GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism-related genes/obesity. Smek1 KO mice were generated to identify the role of SMEK1 in obesity and glucose homeostasis. Cell culture and differentiation of stromal-vascular fractions (SVFs) and 3T3-L1 were used to determine the mechanism. 2-NBDG was used to measure the glucose uptake. Compound C was used to confirm the role of AMPK. We elucidated that SMEK1 was correlated with obesity and adipogenesis. Smek1 deletion enhanced adipogenesis in both SVFs and 3T3-L1. Smek1 KO protected mice from obesity and had protective effects on metabolic disorders, including insulin resistance and inflammation. Smek1 KO mice had lower levels of fasting serum glucose. We found that SMEK1 ablation promoted glucose uptake by increasing p-AMPKα(T172) and the transcription of Glut4 when the effect on AMPK-regulated glucose uptake was due to the PP4 catalytic subunits (PPP4C). Our findings reveal a novel role of SMEK1 in obesity and glucose homeostasis, providing a potential new therapeutic target for obesity and metabolic dysfunction.NEW & NOTEWORTHY Our study clarified the relationship between SMEK1 and obesity for the first time and validated the conclusion in multiple ways by combining available data from public databases, human samples, and animal models. In addition, we clarified the role of SMEK1 in glucose uptake, providing an in-depth interpretation for the study of its function in glucose metabolism.


Assuntos
Proteínas Quinases Ativadas por AMP , Adipogenia , Glucose , Camundongos Knockout , Obesidade , Transdução de Sinais , Animais , Obesidade/metabolismo , Obesidade/genética , Camundongos , Glucose/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Adipogenia/genética , Células 3T3-L1 , Masculino , Camundongos Endogâmicos C57BL , Doenças Metabólicas/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/etiologia , Resistência à Insulina , Tecido Adiposo Branco/metabolismo , Fosfoproteínas Fosfatases
17.
Biomed Pharmacother ; 174: 116585, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38615611

RESUMO

Emerging research into metabolic dysfunction-associated steatotic liver disease (MASLD) up until January 2024 has highlighted the critical role of cuproptosis, a unique cell death mechanism triggered by copper overload, in the disease's development. This connection offers new insights into MASLD's complex pathogenesis, pointing to copper accumulation as a key factor that disrupts lipid metabolism and insulin sensitivity. The identification of cuproptosis as a significant contributor to MASLD underscores the potential for targeting copper-mediated pathways for novel therapeutic approaches. This promising avenue suggests that managing copper levels could mitigate MASLD progression, offering a fresh perspective on treatment strategies. Further investigations into how cuproptosis influences MASLD are essential for unraveling the detailed mechanisms at play and for identifying effective interventions. The focus on copper's role in liver health opens up the possibility of developing targeted therapies that address the underlying causes of MASLD, moving beyond symptomatic treatment to tackle the root of the problem. The exploration of cuproptosis in the context of MASLD exemplifies the importance of understanding metal homeostasis in metabolic diseases and represents a significant step forward in the quest for more effective treatments. This research direction lights path for innovative MASLD management and reversal.


Assuntos
Apoptose , Cobre , Fígado Gorduroso , Animais , Humanos , Cobre/metabolismo , Fígado Gorduroso/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/metabolismo
18.
Zhongguo Zhen Jiu ; 44(3): 333-337, 2024 Mar 12.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38467510

RESUMO

Pancreatic adipose tissue serves as a crucial structural basis for the development of glycolipid metabolic disorders. Understanding the mechanisms underlying pancreatic adipose tissue infiltration and regulatory strategies is essential for early intervention in glycolipid metabolic disorders. Pancreatic adipose tissue functions as a significant medium linking systemic immune metabolism, while the pancreatic vascular system emerges as a novel target for sensing pancreatic immune responses and maintaining the body's energy homeostasis, collectively participating in the development of glycolipid metabolic disorders. Acupuncture possesses potential effects in modulating the interaction between resident macrophages and adipocytes in the pancreas, leading to the reversible reduction of excessive pancreatic adipose accumulation, with its action being vascular-dependent.


Assuntos
Terapia por Acupuntura , Doenças Metabólicas , Humanos , Tecido Adiposo/metabolismo , Adipócitos/metabolismo , Pâncreas , Doenças Metabólicas/terapia , Doenças Metabólicas/metabolismo
19.
Diabetes Metab Res Rev ; 40(3): e3787, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38461408

RESUMO

AIMS: Given the increasing number of individuals developing metabolic dysfunction-associated steatotic liver disease (MASLD) and the low rate of those with progressive liver disease, there is a pressing need to conceive affordable biomarkers to assess MASLD in general population settings. Herein, we aimed to investigate the performance of the ultrasound-derived fat fraction (UDFF) for hepatic steatosis in high-risk individuals. METHODS: A total of 302 Europeans with obesity, type 2 diabetes, or a clinical history of hepatic steatosis were included in the analyses. Clinical, laboratory, and imaging data were collected using standardized procedures during a single screening visit in Rome, Italy. Hepatic steatosis was defined by controlled attenuation parameter (CAP) or ultrasound-based Hamaguchi's score. UDFF performance for hepatic steatosis was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, median (IQR) UDFF was 12% (7-20). UDFF was positively correlated with CAP (ρ = 0.73, p < 0.0001) and Hamaguchi's score (ρ = 0.79, p < 0.0001). Independent predictors of UDFF were circulating triglycerides, alanine aminotransferase (ALT), and ultrasound-measured visceral adipose tissue (VAT). UDFF AUC was 0.89 (0.85-0.93) and 0.92 (0.88-0.95) for CAP- and ultrasound-diagnosed hepatic steatosis, respectively. UDFF AUC for hepatic steatosis was higher than those of fatty liver index (FLI), hepatic steatosis index (HSI), CAP-score (CAPS), and ALT (p < 0.0001). Lower age, ALT, and VAT were associated with discordance between UDFF and ultrasound. CONCLUSIONS: UDFF may be a simple and accurate imaging biomarker to assess hepatic steatosis and monitor changes in hepatic fat content over time or in response to therapeutic interventions beyond clinical trials.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Doenças Metabólicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico por imagem , Fígado , Ultrassonografia/métodos , Curva ROC , Biomarcadores/metabolismo , Doenças Metabólicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/diagnóstico
20.
Theranostics ; 14(5): 2075-2098, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505622

RESUMO

Obesity-related metabolic diseases, including obesity, diabetes, hyperlipidemia, and non-alcoholic fatty liver diseases pose a significant threat to health. However, comprehensive pathogenesis exploration and effective therapy development are impeded by the limited availability of human models. Notably, advances in organoid technology enable the generation of adipose organoids that recapitulate structures and functions of native human adipose tissues to investigate mechanisms and develop corresponding treatments for obesity-related metabolic diseases. Here, we review the general principles, sources, and three-dimensional techniques for engineering adipose organoids, along with strategies to promote maturation. We also outline the application of white adipose organoids, primarily for disease modeling and drug screening, and highlight the therapeutic potential of thermogenic beige and brown adipose organoids in promoting weight loss and glucose and lipid metabolic homeostasis. We also discuss the challenges and prospects in the establishment and bench-to-bedside of adipose organoids, as well as their potential applications.


Assuntos
Doenças Metabólicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Tecido Adiposo Marrom/metabolismo , Obesidade/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Doenças Metabólicas/metabolismo , Termogênese
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