RESUMO
Monogenic familial hypercholesterolemia is characterized by impaired cellular uptake of apolipoprotein B containing lipoproteins. However, its consequences on whole-body cholesterol metabolism are unclear. We investigated cholesterol metabolism in wild-type mice (control) and in knockout (KO) mice for the low-density lipoprotein receptor (LDLR-KO) and for apolipoprotein E (apoE-KO) containing the genetic basis of the C57BL/6J mice, under a cholesterol-free diet. Cholesterol and "non-cholesterol" sterols (cholestanol, desmosterol, and lathosterol) were measured in plasma, tissues, as well as in feces as cholesterol and its bacterial modified products (neutral sterols) using gas chromatography/mass spectrometry, and bile acids were measured by an enzymatic method. Compared to controls, LDLR-KO mice have elevated plasma and whole-body cholesterol concentrations, but total fecal sterols are not modified, characterizing unaltered body cholesterol synthesis together with impaired body cholesterol excretion. ApoE-KO mice presented the highest concentrations of plasma cholesterol, whole-body cholesterol, cholestanol, total fecal sterols, and cholestanol, compatible with high cholesterol synthesis rate; the latter seems attributed to elevated body desmosterol (Bloch cholesterol synthesis pathway). Nonetheless, whole-body lathosterol (Kandutsch-Russel cholesterol synthesis pathway) decreased in both KO models, likely explaining the diminished fecal bile acids. We have demonstrated for the first time quantitative changes of cholesterol metabolism in experimental mouse models that explain differences between LDLR-KO and apoE-KO mice. These findings contribute to elucidate the metabolism of cholesterol in human hypercholesterolemia of genetic origin.
Assuntos
Colestadienóis , Colesterol , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos , Animais , Colestadienóis/sangue , Colestadienóis/metabolismo , Colesterol/sangue , Colesterol/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoERESUMO
This study investigated the influence of sodium restriction and antihypertensive drugs on atherogenesis utilizing hypertensive (H) low-density lipoprotein-receptor knockout mice treated or not with losartan (Los) or hydralazine (Hyd) and fed low-sodium (LS) or normal-sodium (NS) chow. Despite reducing the blood pressure (BP) of H-LS mice, the LS diet caused arterial lipid infiltration due to increased plasma total cholesterol (TC) and triglycerides (TG). Los and Hyd reduced the BP of H-LS mice, and Los effectively prevented arterial injury, likely by reducing plasma TG and nonesterified fatty acids. Aortic lipid infiltration was lower in Los-treated H-LS mice (H-LS+Los) than in normotensive (N)-LS and H-LS mice. Aortic angiotensin II type 1 (AT1) receptor content was greater in H-NS than H-LS mice and in H-LS+Hyd than H-LS+Los mice. Carboxymethyl-lysine (CML) and receptor for advanced glycation end products (RAGE) immunostaining was greater in H-LS than H-NS mice. CML and RAGE levels were lower in LS animals treated with antihypertensive drugs, and Hyd enhanced the AT1 receptor level. Hyd also increased the gene expression of F4/80 but not tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-10, intercellular adhesion molecule-1 or cluster of differentiation 66. The novelty of the current study is that in a murine model of simultaneous hypertension and hyperlipidemia, the pleiotropic effect of chronic, severe sodium restriction elicited aortic damage even with reduced BP. These negative effects on the arterial wall were reduced by AT1 receptor antagonism, demonstrating the influence of angiotensin II in atherogenesis induced by a severely LS diet.
Assuntos
Aterosclerose/etiologia , Pressão Sanguínea , Dieta Hipossódica , Hiperlipidemias/complicações , Hipertensão/prevenção & controle , Animais , Hipertensão/complicações , Camundongos , Camundongos Knockout , Receptores de LDL/genéticaRESUMO
BACKGROUND: According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. MATERIALS AND METHODS: This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. RESULTS: Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. CONCLUSION: These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.
Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Hipercolesterolemia/tratamento farmacológico , Amidas , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteínas B/efeitos dos fármacos , Apolipoproteínas B/metabolismo , Aterosclerose/metabolismo , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Ésteres , Humanos , Hipercolesterolemia/metabolismo , Camundongos , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Coelhos , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/uso terapêuticoRESUMO
BACKGROUND: We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects. METHODS: We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-1HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption. RESULTS: In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-1HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities. CONCLUSIONS: These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.
Assuntos
HDL-Colesterol/sangue , Resistência à Insulina , Insulina/sangue , Adulto , Idoso , Biomarcadores/sangue , Brasil , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/deficiência , VLDL-Colesterol/sangue , Feminino , Voluntários Saudáveis , Humanos , Peso Corporal Ideal , Absorção Intestinal , Lipase/sangue , Metabolismo dos Lipídeos , Erros Inatos do Metabolismo Lipídico/sangue , Lipase Lipoproteica/sangue , Masculino , Pessoa de Meia-Idade , Fosfatidilcolina-Esterol O-Aciltransferase/sangue , Proteínas de Transferência de Fosfolipídeos/sangue , Adulto JovemRESUMO
Assessment of lipid profile parameters has been considered a cornerstone in classifying individuals and populations at risk for cardiovascular disease. Recently, however, preliminary data have raised the possibility of seasonal variations in these parameters, which may cause under- or overestimation. Biological rhythms and seasonal variation of lipid profile was investigated in 227 359 consecutive individuals who underwent health checkups in primary care centers between 2008 and 2010. Plasma low-density lipoprotein cholesterol (LDL-C) >130 mg/dL was 8% more prevalent during winter than summer, with a larger difference among women and middle-aged adults (p < 0.001). High-density lipoprotein cholesterol (HDL-C) <40 mg/dL and triglycerides (TG) >150 mg/dL were respectively 9% and 5% more prevalent during the summer (p < 0.001). Variation amplitude was 3.4 ± 0.3 mg/dL for HDL-C (p = 0.005), 7 ± 2 mg/dL for LDL-C (p = 0.047), and 12 ± 9 mg/dL for TG (p = 0.058). Based on a large population sample, this study confirms the existence of biological rhythms and seasonal variation in lipid profile. This finding must be particularly accounted for in cross-sectional analyses of relative risk, prevalence, or the rate of goal achievement for lipid parameters.
Assuntos
Dislipidemias/epidemiologia , Periodicidade , Estações do Ano , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Brasil/epidemiologia , Criança , Pré-Escolar , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Prevalência , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Fatores de Tempo , Triglicerídeos/sangue , Adulto JovemRESUMO
The development of atherosclerosis and the inflammatory response were investigated in LDLr-KO mice on three high-fat diets (40% energy as fat) for 16 weeks: trans (TRANS), saturated (SAFA) or ω-6 polyunsaturated (PUFA) fats. The following parameters were measured: plasma lipids, aortic root total cholesterol (TC), lesion area (Oil Red-O), ABCA1 content and macrophage infiltration (immunohistochemistry), collagen content (Picrosirius-red) and co-localization of ABCA1 and macrophage (confocal microscopy) besides the plasma inflammatory markers (IL-6, TNF-α) and the macrophage inflammatory response to lipopolysaccharide from Escherichia coli (LPS). As expected, plasma TC and TG concentrations were lower on the PUFA diet than on TRANS or SAFA diets. Aortic intima macrophage infiltration, ABCA1 content, and lesion area on PUFA group were lower compared to TRANS and SAFA groups. Macrophages and ABCA1 markers did not co-localize in the atherosclerotic plaque, suggesting that different cell types were responsible for the ABCA1 expression in plaques. Compared to PUFA, TRANS and SAFA presented higher collagen content and necrotic cores in atherosclerotic plaques. In the artery wall, TC was lower on PUFA compared to TRANS group; free cholesterol was lower on PUFA compared to TRANS and SAFA; cholesteryl ester concentration did not vary amongst the groups. Plasma TNF-α concentration on PUFA and TRANS-fed mice was higher compared to SAFA. No difference was observed in IL-6 concentration amongst groups. Regarding the macrophage inflammatory response to LPS, TRANS and PUFA presented higher culture medium concentrations of IL-6 and TNF-α as compared to SAFA. The PUFA group showed the lowest amount of the anti-inflammatory marker IL-10 compared to TRANS and SAFA groups. In conclusion, PUFA intake prevented atherogenesis, even in a pro-inflammatory condition.
Assuntos
Aterosclerose/prevenção & controle , Ácidos Graxos Ômega-6/uso terapêutico , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Animais , Aorta/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Colesterol/sangue , Colágeno/metabolismo , Dieta Hiperlipídica , Gorduras Insaturadas na Dieta/metabolismo , Gorduras Insaturadas na Dieta/uso terapêutico , Inflamação/metabolismo , Inflamação/prevenção & controle , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Knockout , Receptores de LDL/deficiência , Ácidos Graxos trans/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Metabolic predictors and the atherogenicity of oxidized LDL (oxLDL) and the specific antibodies against oxLDL (oxLDL Ab) are unclear and controversial. METHODS: In 107 adults without atherosclerotic manifestations, we measured oxLDL and oxLDL Ab, and also the activities of CETP, PLTP, lipases and the carotid intima-media thickness (cIMT). Comparisons were performed for the studied parameters between the lowest and the highest tertile of oxLDL and oxLDL Ab, and the relationships between studied variables were evaluated. RESULTS: Subjects with higher oxLDL Ab present reduced hepatic lipase activity and borderline increased cIMT. In the highest oxLDL tertile, besides the higher levels of total cholesterol, LDL-C and apoB100, we found reduced CETP activity and higher cIMT. A significant correlation between oxLDL Ab and cIMT, independent of oxLDL, and a borderline correlation between oxLDL and cIMT independent of oxLDL Ab were found. In the multivariate analysis, apoAI was a significant predictor of oxLDL Ab, in contrast to regulation of oxLDL by apoB100, PLTP and inverse of CETP. CONCLUSIONS: In adults without atherosclerotic disease, the metabolic regulation and carotid atherosclerosis of oxLDL Ab and oxLDL groups, characterized a dual trait in oxLDL Ab, as a contributor to carotid atherosclerosis, much less so than oxidized LDL, and with a modest atheroprotective role.
Assuntos
Anticorpos/sangue , Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/sangue , Colesterol/sangue , Lipoproteínas LDL/sangue , Adulto , Idoso , Análise de Variância , Apolipoproteína B-100/sangue , Transporte Biológico , Doenças das Artérias Carótidas/fisiopatologia , Espessura Intima-Media Carotídea , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , LDL-Colesterol/sangue , Feminino , Humanos , Lipase/metabolismo , Lipoproteínas LDL/imunologia , Fígado/metabolismo , Pessoa de Meia-Idade , Proteínas de Transferência de Fosfolipídeos/metabolismo , Fatores de RiscoRESUMO
The plasma cholesterol-reducing effect of phytosterols (PS) has been recognized in several studies, but the usefulness of PS in preventing coronary heart disease remains controversial, as some investigations claim that the high PS concentrations found in plasma and specific tissues are related to an increased risk of cardiovascular events. It has also been demonstrated that PS may induce inflammation and reduce cholesterol efflux from macrophages, conditions that are directly implicated in the development of atherosclerosis. As to arterial dysfunction and atherosclerosis, some studies have concluded that plasma PS concentrations are unrelated or only weakly related or that PS intake or plasma PS concentrations are harmful. Thus, in light of the National Cholesterol Education Program-ATPIII report, it is necessary to evaluate the relevance of their findings. To this end, we have evaluated the studies conducted on cells, animal models, and humans regarding the influence of PS on the development of atherosclerosis.
Assuntos
Aterosclerose/prevenção & controle , Dieta , Fitosteróis/administração & dosagem , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Colesterol/metabolismo , Colesterol na Dieta/farmacocinética , Dieta/efeitos adversos , Medicina Baseada em Evidências , Humanos , Absorção Intestinal , Camundongos , Modelos Biológicos , Fitosteróis/efeitos adversos , Fitosteróis/farmacocinética , Fatores de Risco , Pesquisa Translacional BiomédicaRESUMO
Estudos epidemiológicos mostram relação inversa entre níveis plasmáticos de HDL-colesterol (HDL-C) e incidência de doença cardiovascular (DCV). O papel antiaterogênico da HDL é atribuído às suas atividades anti-inflamatória, antitrombótica e antioxidante, além de sua participação no transporte reverso de colesterol (TRC), processo pelo qual a HDL remove colesterol dos tecidos periféricos, incluindo macrófagos da íntima arterial, e o transporta para o fígado para ser excretado pela bile. Com base nesses fatos, o HDL-C tornou-se alvo atrativo para a prevenção da DCV. No entanto, o fracasso do torcetrapib, droga que aumenta substancialmente os níveis de HDL-C, em prevenir DCV, além do conhecimento gerado por estudos de modelos animais e doenças monogênicas que afetam a concentração de HDL-C, tem suscitado questionamentos sobre o papel antiaterogênico da HDL. Esta revisão tem como objetivo abordar aspectos atuais do conhecimento da HDL, baseando-se nessas recentes controvérsias.
Epidemiological studies demonstrate an inverse correlation between plasma HDL-cholesterol (HDL-C) concentration and incidence of cardiovascular disease (CVD). The antiatherogenic role of HDL has been attributed to its anti-inflammatory, antithrombotic and antioxidant properties, besides its participation in the reverse cholesterol transport (RCT), whereby cholesterol from peripheral tissues (including macrophages of the arterial intima) is delivered to the liver for excretion in bile. Due to these actions, HDL-C has evolved as an attractive target for prevention of CVD. However, the failure of torcetrapib, drug that substantially increases HDL-C levels, in preventing CVD and data from studies with animal models and with carriers of monogenic disorders affecting HDL-C levels in humans provide conflicting data about HDL being antiatherogenic. This review addresses the current state of knowledge regarding HDL based on these recent controversies.