RESUMO
COVID-19 infections decrease total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I, A-II, and B levels while triglyceride levels may be increased or inappropriately normal for the poor nutritional status. The degree of reduction in total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I are predictive of mortality. With recovery lipid/lipoprotein levels return towards pre-infection levels and studies have even suggested an increased risk of dyslipidemia post-COVID-19 infection. The potential mechanisms for these changes in lipid and lipoprotein levels are discussed. Decreased HDL-C and apolipoprotein A-I levels measured many years prior to COVID-19 infections are associated with an increased risk of severe COVID-19 infections while LDL-C, apolipoprotein B, Lp (a), and triglyceride levels were not consistently associated with an increased risk. Finally, data suggest that omega-3-fatty acids and PCSK9 inhibitors may reduce the severity of COVID-19 infections. Thus, COVID-19 infections alter lipid/lipoprotein levels and HDL-C levels may affect the risk of developing COVID-19 infections.
Assuntos
COVID-19 , Pró-Proteína Convertase 9 , Humanos , Triglicerídeos , Apolipoproteína A-I , LDL-Colesterol , Lipoproteínas , HDL-ColesterolRESUMO
Elevated low-density lipoprotein cholesterol (LDL-C) levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) and lowering LDL-C levels reduces the risk of ASCVD. In patients with elevated LDL-C levels it is important to consider whether lifestyle, other medical conditions, medications, or genetic factors could be causing or contributing to the elevation. There are guidelines from various organizations outlining the approach to lowering LDL-C levels but while these guidelines agree on many issues there are numerous areas where recommendations are discordant. In this review, we outline several principles that will help in deciding who and how to treat patients with elevated LDL-C levels. Specifically, we discuss evidence indicating that the sooner one initiates therapy the better and the greater the reduction in LDL-C the better. Additionally, the higher the LDL-C level and the higher the risk of ASCVD, the greater the benefits of treatment. Using these principles will help in making decisions regarding the treatment of LDL-C levels.
Assuntos
Anticolesterolemiantes , Aterosclerose , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol/uso terapêutico , Colesterol/uso terapêutico , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Aterosclerose/tratamento farmacológico , Anticolesterolemiantes/uso terapêuticoRESUMO
Elevated triglyceride levels increase the risk of arteriosclerotic cardiovascular disease (ASCVD) and severely elevated triglyceride levels also increase the risk of triglyceride-induced pancreatitis. Although substantially reducing triglyceride levels will prevent pancreatitis, whether lowering triglycerides per se will reduce CVD risk is unclear. In this review, we outline several principles that will help in deciding who and how to treat patients with elevated triglyceride levels in order to prevent both ASCVD and pancreatitis. Using these principles will help in making decisions regarding the treatment of elevated triglyceride levels.
Assuntos
Hipertrigliceridemia , Pancreatite , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Pancreatite/etiologia , Pancreatite/prevenção & controle , TriglicerídeosRESUMO
The exogenous lipoprotein pathway starts with the incorporation of dietary lipids into chylomicrons in the intestine. Chylomicron triglycerides are metabolized in muscle and adipose tissue and chylomicron remnants are formed, which are removed by the liver. The endogenous lipoprotein pathway begins in the liver with the formation of very low-density lipoprotein particles (VLDL). VLDL triglycerides are metabolized in muscle and adipose tissue forming intermediate-density lipoprotein (IDL), which may be taken up by the liver or further metabolized to low-density lipoprotein (LDL). Reverse cholesterol transport begins with the formation of nascent high-density lipoprotein (HDL) by the liver and intestine that acquire cholesterol from cells resulting in mature HDL. The HDL then transports the cholesterol to the liver either directly or indirectly by transferring the cholesterol to VLDL or LDL.
Assuntos
Colesterol , Lipoproteínas , Colesterol/metabolismo , Humanos , Lipoproteínas/metabolismo , Lipoproteínas LDL/metabolismo , Triglicerídeos/metabolismoRESUMO
Studying skin barrier function is central to our understanding of many skin disorders. The past decade has seen a surge of skin barrier related investigative work. Genetic, biochemical and cell biology experiments have added much evidence to the importance of the barrier in disease pathogenesis of a variety of disorders including ichthyosis, atopic dermatitis and psoriasis. However, functional assays prove ever more important to demonstrate relevance of any of these findings. A paper published by Monash and Blank 60 years ago describes a stress test of the skin barrier, measuring skin barrier recovery, a functional test of tremendous implications. This seminal paper has not been cited for almost 15 years, time to acknowledge its critical importance and to review the relevance of this method today.
Assuntos
Epiderme/metabolismo , Fenômenos Fisiológicos da Pele , Estresse Fisiológico , Técnicas e Procedimentos Diagnósticos , Humanos , Permeabilidade , Recuperação de Função Fisiológica , Perda Insensível de ÁguaRESUMO
PURPOSE OF REVIEW: Drugs to lower LDL-C levels are very widely used. In this brief review, I will use selected recent studies to delineate several important principles that provide a rationale for how to maximize the benefits of using LDL-C lowering drugs to reduce cardiovascular disease. The focus will be on using statins, ezetimibe, and PCSK9 monoclonal antibodies as recent studies have predominantly utilized these agents. RECENT FINDINGS: The key principles to consider when using LDL-C-lowering drugs to reduce cardiovascular disease are: the lower the LDL-C the better; the sooner and the longer one lowers LDL-C the better; the higher the risk of cardiovascular disease the greater the absolute benefit; the higher the baseline LDL-C the greater the absolute benefit; and compared with the benefits of cholesterol-lowering drugs on reducing cardiovascular disease the risk of side effects is very modest. SUMMARY: Understanding and employing these key concepts in caring for patients will allow one to use cholesterol-lowering drugs wisely to maximize the reduction of cardiovascular events.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/antagonistas & inibidores , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/imunologia , Anticorpos Monoclonais/uso terapêutico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/genética , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Inibidores de PCSK9Assuntos
Diarreia/etiologia , Gastrinoma/diagnóstico , Neoplasias Hepáticas/secundário , Fígado/diagnóstico por imagem , Neoplasias Primárias Desconhecidas/diagnóstico , Síndrome de Zollinger-Ellison/diagnóstico , Abdome/diagnóstico por imagem , Dor Abdominal/etiologia , Idoso , Análise Química do Sangue , Doença Crônica , Diagnóstico Diferencial , Gastrinoma/complicações , Gastrinoma/diagnóstico por imagem , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética , Masculino , Neoplasias Primárias Desconhecidas/complicações , Policitemia/complicações , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Síndrome de Zollinger-Ellison/complicaçõesRESUMO
Even though elderly populations lack visible or other clinical signs of inflammation, their serum cytokine and C-reactive protein levels typically are elevated. However, the origin of age-associated systemic inflammation is unknown. Our previous studies showed that abnormalities in epidermal function provoke cutaneous inflammation, and because intrinsically aged skin displays compromised permeability barrier homeostasis and reduced stratum corneum hydration, we hypothesized here that epidermal dysfunction could contribute to the elevations in serum cytokines in the elderly. Our results show first that acute disruption of the epidermal permeability barrier in young mice leads not only to a rapid increase in cutaneous cytokine mRNA expression but also an increase in serum cytokine levels. Second, cytokine levels in both the skin and serum increase in otherwise normal, aged mice (>12 months). Third, expression of tumor necrosis factor-α and amyloid A mRNA levels increased in the epidermis, but not in the liver, in parallel with a significant elevation in serum levels of cytokines. Fourth, disruption of the permeability barrier induced similar elevations in epidermal and serum cytokine levels in normal and athymic mice, suggesting that T cells play a negligible role in the elevations in cutaneous and serum inflammatory cytokines induced by epidermal dysfunction. Fifth, correction of epidermal function significantly reduced cytokine levels not only in the skin but also in the serum of aged mice. Together, these results indicate that the sustained abnormalities in epidermal function in chronologically aged skin contribute to the elevated serum levels of inflammatory cytokines, potentially predisposing the elderly to the subsequent development or exacerbation of chronic inflammatory disorders.
Assuntos
Envelhecimento/fisiologia , Permeabilidade Capilar/fisiologia , Citocinas/sangue , Epiderme/metabolismo , Epiderme/patologia , Amiloide/sangue , Análise de Variância , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Glicerol/farmacologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Distribuição Aleatória , Estatísticas não ParamétricasRESUMO
PURPOSE OF REVIEW: Studies have shown that chronic inflammatory disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis are associated with an increased risk of atherosclerotic cardiovascular disease. The mechanism by which inflammation increases cardiovascular disease is likely multifactorial but changes in HDL structure and function that occur during inflammation could play a role. RECENT FINDINGS: HDL levels decrease with inflammation and there are marked changes in HDL-associated proteins. Serum amyloid A markedly increases whereas apolipoprotein A-I, lecithin:cholesterol acyltransferase, cholesterol ester transfer protein, paraoxonase 1, and apolipoprotein M decrease. The exact mechanism by which inflammation decreases HDL levels is not defined but decreases in apolipoprotein A-I production, increases in serum amyloid A, increases in endothelial lipase and secretory phospholipase A2 activity, and decreases in lecithin:cholesterol acyltransferase activity could all contribute. The changes in HDL induced by inflammation reduce the ability of HDL to participate in reverse cholesterol transport and protect LDL from oxidation. SUMMARY: During inflammation multiple changes in HDL structure occur leading to alterations in HDL function. In the short term, these changes may be beneficial resulting in an increase in cholesterol in peripheral cells to improve host defense and repair but over the long term these changes may increase the risk of atherosclerosis.
Assuntos
Inflamação/metabolismo , Lipoproteínas HDL/química , Lipoproteínas HDL/metabolismo , Animais , Transporte Biológico , Colesterol/metabolismo , Humanos , OxirreduçãoAssuntos
Doença de Graves/diagnóstico , Doença de Hashimoto/tratamento farmacológico , Glândula Tireoide/patologia , Tireoidite Autoimune/diagnóstico , Tiroxina/uso terapêutico , Adulto , Progressão da Doença , Fadiga/etiologia , Doença de Graves/imunologia , Doença de Hashimoto/diagnóstico , Frequência Cardíaca/fisiologia , Humanos , Imunoglobulinas Estimuladoras da Glândula Tireoide/análise , Imunoglobulinas Estimuladoras da Glândula Tireoide/imunologia , Iodeto Peroxidase/sangue , Iodeto Peroxidase/imunologia , Masculino , Cintilografia , Tireoglobulina/sangue , Tireoglobulina/imunologia , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/imunologia , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tiroxina/administração & dosagem , Ultrassonografia , Redução de Peso/fisiologiaRESUMO
BACKGROUND: High-density lipoprotein (HDL) particles have properties beyond reverse cholesterol transport. We hypothesized that their protection extends to inflammation-related disease. The predictive value of HDL particle subclasses and inflammatory markers was studied for noncardiovascular, noncancer chronic inflammation-related death and hospitalization, and for incident cardiovascular disease (CVD). METHODS AND RESULTS: A multiethnic, multicenter, prospective observational study was conducted in 6475 men and women (aged 45 to 84 years) free of known CVD at baseline with median follow-up of 10.1 years. Fasting venous samples were analyzed for baseline lipid profile and lipoprotein particles. We focused on the HDL family of variables (small-, medium-, and large-diameter HDL particles and HDL cholesterol). Analyses identified the sum of small- plus medium-diameter HDL particles as important. Small- plus medium-diameter HDL particles were inversely associated with diagnostic code-based noncardiovascular, noncancer chronic inflammation-related death and hospitalization (n=1054) independent of covariates: relative risk per SD 0.85 (95% CI: 0.79 to 0.91, P<0.0001). Small- plus medium-diameter HDL particles were also associated with adjudicated fatal and nonfatal coronary heart disease events (n=423): relative risk per SD 0.88 (95% CI 0.77 to 0.98, P=0.02). CONCLUSIONS: Small- plus medium-diameter HDL particles are an independent predictor for noncardiovascular, noncancer chronic inflammation-related death and hospitalization and for coronary heart disease events in subjects initially free of overt CVD. These findings support the hypothesis that smaller HDL particles of diameter <9.4 nm have anti-inflammatory properties in the general population.
Assuntos
Aterosclerose/sangue , Doença das Coronárias/sangue , Mediadores da Inflamação/sangue , Inflamação/sangue , Lipoproteínas HDL/sangue , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/diagnóstico , Aterosclerose/etnologia , Aterosclerose/mortalidade , Biomarcadores/sangue , HDL-Colesterol/sangue , Doença das Coronárias/diagnóstico , Doença das Coronárias/etnologia , Doença das Coronárias/mortalidade , Progressão da Doença , Feminino , Hospitalização , Humanos , Inflamação/diagnóstico , Inflamação/etnologia , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Prognóstico , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
The cutaneous permeability barrier is essential for life and perturbations in this barrier are repaired rapidly. After minimal injury to the stratum corneum alterations in the calcium concentration in the outer epidermis are the primary signal inducing this repair response. In this issue, studies demonstrate that Toll-like receptor 3 has an important role in signaling permeability barrier repair following injury induced by UVB irradiation.
Assuntos
Pele/efeitos da radiação , Receptor 3 Toll-Like/fisiologia , Raios Ultravioleta/efeitos adversos , Animais , Feminino , MasculinoRESUMO
Multilayered human keratinocyte cultures increasingly are used to model human epidermis. Until now, studies utilizing human epidermal equivalents (HEEs) have been limited because previous preparations do not establish a normal epidermal permeability barrier. In this report, we show that reducing environmental humidity to 50% relative humidity yields HEEs that closely match human postnatal epidermis and have enhanced repair of the permeability barrier. These cultures display low transepidermal water loss and possess a calcium and pH gradient that resembles those seen in human epidermis. These cultures upregulate glucosylceramide synthase and make normal-appearing lipid lamellar bilayers. The epidermal permeability barrier of these cultures can be perturbed, using the identical tools previously described for human skin, and recover in the same time course seen during in vivo barrier recovery. These cultures will be useful for basic and applied studies on epidermal barrier function.
Assuntos
Epiderme/crescimento & desenvolvimento , Epiderme/fisiologia , Umidade , Células Cultivadas , Células Epidérmicas , Epiderme/ultraestrutura , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Íons , Masculino , Proteínas/metabolismoRESUMO
Many of the beneficial and adverse effects of niacin are mediated via a G protein receptor, G protein-coupled receptor 109A/hydroxycarboxylic acid 2 receptor (GPR109A/HCA2), which is highly expressed in adipose tissue and macrophages. Here we demonstrate that immune activation increases GPR109A/HCA2 expression. Lipopolysaccharide (LPS), TNF, and interleukin (IL) 1 increase GPR109A/HCA2 expression 3- to 5-fold in adipose tissue. LPS also increased GPR109A/HCA2 mRNA levels 5.6-fold in spleen, a tissue rich in macrophages. In peritoneal macrophages and RAW cells, LPS increased GPR109A/HCA2 mRNA levels 20- to 80-fold. Zymosan, lipoteichoic acid, and polyinosine-polycytidylic acid, other Toll-like receptor activators, and TNF and IL-1 also increased GPR109A/HCA2 in macrophages. Inhibition of the myeloid differentiation factor 88 or TIR-domain-containing adaptor protein inducing IFNß pathways both resulted in partial inhibition of LPS stimulation of GPR109A/HCA2, suggesting that LPS signals an increase in GPR109A/HCA2 expression by both pathways. Additionally, inhibition of NF-κB reduced the ability of LPS to increase GPR109A/HCA2 expression by â¼50% suggesting that both NF-κB and non-NF-κB pathways mediate the LPS effect. Finally, preventing the LPS-induced increase in GPR109A/HCA2 resulted in an increase in TG accumulation and the expression of enzymes that catalyze TG synthesis. These studies demonstrate that inflammation stimulates GPR109A/HCA2 and there are multiple intracellular signaling pathways that mediate this effect. The increase in GPR109A/HCA2 that accompanies macrophage activation inhibits the TG accumulation stimulated by macrophage activation.
Assuntos
Modelos Animais de Doenças , Gordura Intra-Abdominal/metabolismo , Ativação de Macrófagos , Macrófagos Peritoneais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Transdução de Sinais , Regulação para Cima , Células 3T3-L1 , Animais , Linhagem Celular Transformada , Células Cultivadas , Feminino , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/patologia , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/metabolismo , Infecções por Bactérias Gram-Positivas/patologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Metabolismo dos Lipídeos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Micoses/imunologia , Micoses/metabolismo , Micoses/patologia , Interferência de RNA , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Receptores Nicotínicos/genética , Viroses/imunologia , Viroses/metabolismo , Viroses/patologiaRESUMO
Acute psychological stress (PS) mobilizes metabolic responses that are of immediate benefit to the host, but the current medical paradigm holds that PS exacerbates systemic and cutaneous inflammatory disorders. Although the adverse consequences of PS are usually attributed to neuroimmune mechanisms, PS also stimulates an increase in endogenous glucocorticoids (GCs) that compromises permeability barrier homeostasis, stratum corneum cohesion, wound healing, and epidermal innate immunity in normal skin. Yet, if such PS-induced increases in GC were uniformly harmful, natural selection should have eliminated this component of the stress response. Hence, we hypothesized here instead that stress-induced elevations in endogenous GC could benefit, rather than aggravate, cutaneous function and reduce inflammation in three immunologically diverse mouse models of inflammatory diseases. Indeed, superimposed exogenous (motion-restricted) stress reduced, rather than aggravated inflammation and improved epidermal function in all three models, even normalizing serum IgE levels in the atopic dermatitis model. Elevations in endogenous GC accounted for these apparent benefits, because coadministration of mifepristone prevented stress-induced disease amelioration. Thus, exogenous stress can benefit rather than aggravate cutaneous inflammatory dermatoses through the anti-inflammatory activity of increased endogenous GC.
Assuntos
Glucocorticoides/metabolismo , Dermatopatias/metabolismo , Dermatopatias/psicologia , Pele/metabolismo , Estresse Psicológico/metabolismo , Animais , Permeabilidade da Membrana Celular/fisiologia , Modelos Animais de Doenças , Feminino , Homeostase/fisiologia , Imunidade Inata/fisiologia , Imunoglobulina E/sangue , Masculino , Camundongos , Camundongos Pelados , Camundongos Endogâmicos C57BL , Pele/fisiopatologia , Dermatopatias/fisiopatologia , Estresse Psicológico/fisiopatologia , Cicatrização/fisiologiaRESUMO
Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, ß-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression.
Assuntos
Ácidos/metabolismo , Epiderme/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Homeostase/genética , Melanócitos/metabolismo , Pigmentação da Pele/fisiologia , Animais , Ceramidas/biossíntese , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Células Epidérmicas , Feminino , Glucosilceramidase/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Queratinócitos/metabolismo , Bicamadas Lipídicas/metabolismo , Masculino , Melaninas/metabolismo , Melanócitos/ultraestrutura , Camundongos Pelados , Microscopia Eletrônica , Técnicas de Cultura de Órgãos , Comunicação Parácrina/fisiologia , Permeabilidade , Esfingomielina Fosfodiesterase/metabolismoRESUMO
There is a marked increase in cytokines, including interferon gamma, in cutaneous diseases such as atopic dermatitis and psoriasis. In this issue of the Journal, Tawada and colleagues demonstrate that the quantity of ultra long-chain ceramides in the stratum corneum, which play a key role in maintaining the permeability barrier, is reduced in atopic dermatitis and psoriasis. Further, they demonstrate that interferon gamma decreases the expression of the enzymes required for the synthesis of these ultra long-chain ceramides (ELOVLs and ceramide synthase 3). These results suggest that an increase in interferon gamma by decreasing the key enzymes required for the synthesis of ultra long-chain ceramides could further impair permeability barrier function, thereby exacerbating the pathological changes.