Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Arterioscler Thromb Vasc Biol ; 42(2): 127-144, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34911361

RESUMO

OBJECTIVE: Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout (Ldlr-/-), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. CONCLUSIONS: Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Flavonas/farmacologia , Hiperlipidemias/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Feminino , Flavonas/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Período Pós-Prandial , Substâncias Protetoras/uso terapêutico , Triglicerídeos/sangue , Triglicerídeos/metabolismo
2.
J Lipid Res ; 61(3): 387-402, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31964763

RESUMO

Obesity, dyslipidemia, and insulin resistance, the increasingly common metabolic syndrome, are risk factors for CVD and type 2 diabetes that warrant novel therapeutic interventions. The flavonoid nobiletin displays potent lipid-lowering and insulin-sensitizing properties in mice with metabolic dysfunction. However, the mechanisms by which nobiletin mediates metabolic protection are not clearly established. The central role of AMP-activated protein kinase (AMPK) as an energy sensor suggests that AMPK is a target of nobiletin. We tested the hypothesis that metabolic protection by nobiletin required phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in mouse hepatocytes, in mice deficient in hepatic AMPK (Ampkß1-/-), in mice incapable of inhibitory phosphorylation of ACC (AccDKI), and in mice with adipocyte-specific AMPK deficiency (iß1ß2AKO). We fed mice a high-fat/high-cholesterol diet with or without nobiletin. Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis. Despite loss of ACC phosphorylation in Ampkß1-/- hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver. In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkß1-/-, AccDKI, and iß1ß2AKO mice to the same extent as in WT controls. Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation. These studies further underscore the therapeutic potential of nobiletin and begin to clarify possible mechanisms.


Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Antioxidantes/farmacologia , Citrus/química , Flavonas/farmacologia , Substâncias Protetoras/farmacologia , Proteínas Quinases Ativadas por AMP/deficiência , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/química , Dieta Hiperlipídica/efeitos adversos , Flavonas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/química
3.
Atherosclerosis ; 286: 60-70, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31102954

RESUMO

BACKGROUND AND AIMS: Naringenin is a citrus-derived flavonoid with lipid-lowering and insulin-sensitizing effects leading to athero-protection in Ldlr-/- mice fed a high-fat diet. However, the ability of naringenin to promote atherosclerosis regression is unknown. In the present study, we assessed the capacity of naringenin to enhance regression in Ldlr-/- mice with diet-induced intermediate atherosclerosis intervened with a chow diet. METHODS: Male Ldlr-/- mice were fed a high-fat, cholesterol-containing (HFHC) diet for 12 weeks to induce intermediate atherosclerosis and metabolic dysfunction. Subsequently, a group of these mice were sacrificed for baseline analyses and the remainder either 1) continued on the HFHC diet, 2) switched to a chow diet or 3) switched to chow diet supplemented with naringenin. RESULTS: After 12 weeks induction, intermediate lesions developed in the aortic sinus. Intervention with chow alone slowed lesion growth, while intervention with naringenin-supplemented chow completely halted lesion growth. Lesions were characterized by features of improved morphology. Compared to chow alone, naringenin reduced plaque macrophages and modestly increased smooth muscle cells. Investigating processes that contributed to improved plaque morphology, we showed naringenin further reduced plasma triglycerides and cholesterol compared to chow alone. Furthermore, elevated monocytosis and myelopoiesis were further corrected by intervention with naringenin compared to chow alone. Metabolically, naringenin enhanced the correction of insulin resistance, hepatic steatosis and obesity compared to chow alone, potentially contributing to enhanced regression. CONCLUSIONS: Naringenin supplementation to chow enhances atherosclerosis regression in male Ldlr-/- mice. These studies further underscore the potential therapeutic utility of naringenin.


Assuntos
Aterosclerose/tratamento farmacológico , Flavanonas/uso terapêutico , Animais , Aterosclerose/etiologia , Dieta Hiperlipídica , Masculino , Camundongos , Indução de Remissão
4.
Mol Nutr Food Res ; 63(6): e1800833, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30578663

RESUMO

SCOPE: Naringenin is a citrus-derived flavonoid that has potent lipid-lowering and insulin-sensitizing effects in obese mouse models of metabolic dysfunction. However, in these models, a significant effect of naringenin supplementation is the prevention of weight gain, which in itself can confer metabolic protection. Therefore, in the present study, the effect of naringenin supplementation in lean, chow-fed Ldlr-/- mice is investigated. METHODS AND RESULTS: In Ldlr-/- mice with isocaloric food consumption, treatment with naringenin for 8 weeks reduces body weight and adiposity compared to littermate controls pair-fed the chow diet alone. Furthermore, naringenin treatment reduces plasma lipids and enhances insulin sensitivity compared to chow-fed controls. Metabolic cage studies reveal that naringenin-treated mice have elevated energy expenditure with no change in ambulatory activity. Additionally, naringenin-treated mice have an increased respiratory exchange ratio and food consumption during the dark cycle. Treatment increases the expression of fatty acid oxidation genes in liver, and increased ß-hydroxybutyrate concentrations in plasma, indicating that one mechanism through which naringenin mediates metabolic improvement is enhanced hepatic fatty acid oxidation. CONCLUSIONS: These studies highlight the potential therapeutic utility of naringenin and suggest that this flavonoid maintains potent metabolic properties in the absence of obesity or a high-fat diet.


Assuntos
Adiposidade/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Flavanonas/farmacologia , Adiposidade/fisiologia , Animais , Suplementos Nutricionais , Insulina/sangue , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Oxirredução , Receptores de LDL/genética
5.
Curr Opin Lipidol ; 30(1): 1-9, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30586346

RESUMO

PURPOSE OF REVIEW: Bempedoic acid has emerged as a potent inhibitor of ATP-citrate lyase (ACLY), a target for the reduction of LDL cholesterol (LDL-C). We review the impact of bempedoic acid treatment on lipoprotein metabolism and atherosclerosis in preclinical models and patients with hypercholesterolemia. RECENT FINDINGS: The liver-specific activation of bempedoic acid inhibits ACLY, a key enzyme linking glucose catabolism to lipogenesis by catalyzing the formation of acetyl-CoA from mitochondrial-derived citrate for de novo synthesis of fatty acids and cholesterol. Adenosine monophosphate-activated protein kinase activation by bempedoic acid is not required for its lipid-regulating effects in vivo. Mendelian randomization of large human study cohorts has validated ACLY inhibition as a target for LDL-C lowering and atheroprotection. In rodents, bempedoic acid decreases plasma cholesterol and triglycerides, and prevents hepatic steatosis. In apolipoprotein E-deficient (Apoe) mice, LDL receptor-deficient (Ldlr) mice and LDLR-deficient miniature pigs, bempedoic acid reduces LDL-C and attenuates atherosclerosis. LDLR expression and activity are increased in primary human hepatocytes and in Apoe mouse liver treated with bempedoic acid suggesting a mechanism for LDL-C lowering, although additional pathways are likely involved. Phase 2 and 3 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients. Treatment does not affect plasma concentrations of triglyceride or other lipoproteins. SUMMARY: The LDL-C-lowering and attenuated atherosclerosis in animal models and reduced LDL-C in hypercholesterolemic patients has validated ACLY inhibition as a therapeutic strategy. Positive results from phase 3 long-term cardiovascular outcome trials in high-risk patients are required for bempedoic acid to be approved for prevention of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Lipoproteínas/metabolismo , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Animais , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Terapia de Alvo Molecular , Triglicerídeos/metabolismo
6.
J Lipid Res ; 59(9): 1714-1728, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30008441

RESUMO

Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in Ldlr-/- mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in Ldlr-/- mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.


Assuntos
Aterosclerose/complicações , Citrus/química , Flavonoides/farmacologia , Síndrome Metabólica/complicações , Obesidade/complicações , Obesidade/tratamento farmacológico , Receptores de LDL/deficiência , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Peso Corporal/efeitos dos fármacos , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Flavonoides/uso terapêutico , Hiperlipidemias/complicações , Resistência à Insulina , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/patologia
7.
Arterioscler Thromb Vasc Biol ; 38(5): 1178-1190, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29449335

RESUMO

OBJECTIVE: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia. APPROACH AND RESULTS: Gene targeting has been used to generate Yucatan miniature pigs heterozygous (LDLR+/-) or homozygous (LDLR-/-) for LDL receptor deficiency (ExeGen). LDLR+/- and LDLR-/- pigs were fed a high-fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or BemA for 160 days. In LDLR+/- pigs, compared with placebo, BemA decreased plasma cholesterol and LDL-C up to 40% and 61%, respectively. In LDLR-/- pigs, in which plasma cholesterol and LDL-C were 5-fold higher than in LDLR+/- pigs, BemA decreased plasma cholesterol and LDL-C up to 27% and 29%, respectively. Plasma levels of triglycerides and high-density lipoprotein cholesterol, fasting glucose and insulin, and liver lipids were unaffected by treatment in either genotype. In the aorta of LDLR+/- pigs, BemA robustly attenuated en face raised lesion area (-58%) and left anterior descending coronary artery cross-sectional lesion area (-40%). In LDLR-/- pigs, in which lesions were substantially more advanced, BemA decreased aortic lesion area (-47%) and left anterior descending coronary artery lesion area (-48%). CONCLUSIONS: In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both LDLR+/- and LDLR-/- miniature pigs.


Assuntos
Anticolesterolemiantes/farmacologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Doença da Artéria Coronariana/prevenção & controle , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Receptores de LDL/deficiência , Animais , Animais Geneticamente Modificados , Anticolesterolemiantes/farmacocinética , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Ácidos Dicarboxílicos/farmacocinética , Modelos Animais de Doenças , Regulação para Baixo , Ácidos Graxos/farmacocinética , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino , Fenótipo , Placa Aterosclerótica , Receptores de LDL/genética , Suínos , Porco Miniatura
8.
Arterioscler Thromb Vasc Biol ; 37(4): 647-656, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28153881

RESUMO

OBJECTIVE: Bempedoic acid (ETC-1002, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel low-density lipoprotein cholesterol-lowering compound. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. In this study, we tested the hypothesis that bempedoic acid would prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis. APPROACH AND RESULTS: Ldlr-/- mice were fed a high-fat, high-cholesterol diet (42% kcal fat, 0.2% cholesterol) supplemented with bempedoic acid at 0, 3, 10 and 30 mg/kg body weight/day. Treatment for 12 weeks dose-dependently attenuated diet-induced hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity. Compared to high-fat, high-cholesterol alone, the addition of bempedoic acid decreased plasma triglyceride (up to 64%) and cholesterol (up to 50%) concentrations, and improved glucose tolerance. Adiposity was significantly reduced with treatment. In liver, bempedoic acid prevented cholesterol and triglyceride accumulation, which was associated with increased fatty acid oxidation and reduced fatty acid synthesis. Hepatic gene expression analysis revealed that treatment significantly increased expression of genes involved in fatty acid oxidation while suppressing inflammatory gene expression. In full-length aorta, bempedoic acid markedly suppressed cholesteryl ester accumulation, attenuated the expression of proinflammatory M1 genes and attenuated the iNos/Arg1 ratio. Treatment robustly attenuated atherosclerotic lesion development in the aortic sinus by 44%, with beneficial changes in morphology, characteristic of earlier-stage lesions. CONCLUSIONS: Bempedoic acid effectively prevents plasma and tissue lipid elevations and attenuates the onset of inflammation, leading to the prevention of atherosclerotic lesion development in a mouse model of metabolic dysregulation.


Assuntos
ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Aterosclerose/prevenção & controle , Ácidos Dicarboxílicos/farmacologia , Dieta Hiperlipídica , Dislipidemias/prevenção & controle , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/farmacologia , Inflamação/prevenção & controle , Fígado/efeitos dos fármacos , Obesidade/prevenção & controle , Receptores de LDL/deficiência , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/genética , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Inflamação/sangue , Inflamação/enzimologia , Inflamação/genética , Mediadores da Inflamação/sangue , Insulina/sangue , Lipídeos/sangue , Fígado/enzimologia , Masculino , Camundongos Knockout , Obesidade/sangue , Obesidade/enzimologia , Obesidade/genética , Fenótipo , Receptores de LDL/genética , Fatores de Tempo
9.
Endocrinology ; 156(6): 2087-102, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25774553

RESUMO

The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21(-/-) mice. HFD-fed Fgf21(-/-) mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo.


Assuntos
Fígado Gorduroso/prevenção & controle , Fatores de Crescimento de Fibroblastos/metabolismo , Flavanonas/uso terapêutico , Intolerância à Glucose/prevenção & controle , Obesidade/prevenção & controle , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Masculino , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo
10.
J Lipid Res ; 55(7): 1254-66, 2014 07.
Artigo em Inglês | MEDLINE | ID: mdl-24864274

RESUMO

PPARδ regulates systemic lipid homeostasis and inflammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPARδ agonist corrects hepatic steatosis induced by a high-fat, cholesterol-containing (HFHC) diet. Ldlr(-/-) mice were fed a chow or HFHC diet (42% fat, 0.2% cholesterol) for 4 weeks. For an additional 8 weeks, the HFHC group was fed HFHC or HFHC plus GW1516 (3 mg/kg/day). GW1516-intervention significantly attenuated liver TG accumulation by induction of FA ß-oxidation and attenuation of FA synthesis. In primary mouse hepatocytes, GW1516 treatment stimulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in WT hepatocytes, but not AMPKß1(-/-) hepatocytes. However, FA oxidation was only partially reduced in AMPKß1(-/-) hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPARδ-mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPKß1(-/-) hepatocytes. HFHC-fed animals were hyperinsulinemic and exhibited selective hepatic insulin resistance, which contributed to elevated fasting FA synthesis and hyperglycemia. GW1516 intervention normalized fasting hyperinsulinemia and selective hepatic insulin resistance and attenuated fasting FA synthesis and hyperglycemia. The HFHC diet polarized the liver toward a proinflammatory M1 state, which was reversed by GW1516 intervention. Thus, PPARδ agonist treatment inhibits the progression of preestablished hepatic steatosis.


Assuntos
Gorduras na Dieta/efeitos adversos , Ácidos Graxos/biossíntese , Fígado Gorduroso/metabolismo , Resistência à Insulina , Lipogênese/efeitos dos fármacos , PPAR delta/metabolismo , Receptores de LDL/metabolismo , Animais , Gorduras na Dieta/farmacologia , Ácidos Graxos/genética , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Lipogênese/genética , Camundongos , Camundongos Knockout , Oxirredução/efeitos dos fármacos , PPAR delta/genética , Receptores de LDL/genética
11.
Arterioscler Thromb Vasc Biol ; 34(1): 52-60, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24158519

RESUMO

OBJECTIVE: The peroxisome proliferator-activated receptor (PPAR) δ regulates systemic lipid homeostasis and inflammation. However, the ability of PPARδ agonists to improve the pathology of pre-established lesions and whether PPARδ activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARδ agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle α-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARδ-specific gene Adfp but not PPARα- or γ-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine Arg1, and attenuated the iNos/Arg1 ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress. CONCLUSIONS: Intervention with a PPARδ agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis.


Assuntos
Anti-Inflamatórios/farmacologia , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Resistência à Insulina , PPAR delta/agonistas , Receptores de LDL/deficiência , Tiazóis/farmacologia , Animais , Aortite/sangue , Aortite/etiologia , Aortite/genética , Aortite/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Glicemia/metabolismo , Colesterol na Dieta , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Dislipidemias/metabolismo , Mediadores da Inflamação/metabolismo , Insulina/sangue , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR delta/metabolismo , Receptores de LDL/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
12.
J Lipid Res ; 54(3): 711-724, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23269394

RESUMO

Obesity-associated chronic inflammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates inflammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus flavonoid naringenin to prevent these cholesterol-induced perturbations is unknown. To assess the ability of naringenin to prevent the amplified inflammatory response and atherosclerosis induced by dietary cholesterol, male Ldlr⁻/⁻ mice were fed either a cholesterol-enriched high-fat or low-fat diet supplemented with 3% naringenin for 12 weeks. Naringenin, through induction of hepatic fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and hyperlipidemia induced by both cholesterol-rich diets. Naringenin attenuated hepatic macrophage infiltration and inflammation stimulated by dietary cholesterol. Insulin resistance, adipose tissue expansion, and inflammation were alleviated by naringenin. Naringenin attenuated the cholesterol-induced formation of both foam cells and expression of inflammatory markers in peritoneal macrophages. Naringenin significantly decreased atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic lipids and a reversal of aortic inflammation. We demonstrate that in mice fed cholesterol-enriched diets, naringenin attenuates peripheral and systemic inflammation, leading to protection from atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of cholesterol-induced metabolic dysregulation.


Assuntos
Aterosclerose/induzido quimicamente , Aterosclerose/prevenção & controle , Colesterol/efeitos adversos , Flavanonas/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Animais , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/prevenção & controle , Flavonoides/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Receptores de LDL/metabolismo
13.
Arterioscler Thromb Vasc Biol ; 32(12): 2919-28, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23023367

RESUMO

OBJECTIVE: Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients at risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator-activated receptor (PPAR) δ activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression. METHODS AND RESULTS: THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARδ activation. PPARδ agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced ß-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1ß, macrophage inflammatory protein 1α, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPARδ agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen-activated protein kinase (MAPK)(erk) and AKT/forkhead box protein O1 signaling. CONCLUSIONS: The combined PPARδ-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis.


Assuntos
Células Espumosas/metabolismo , Células Espumosas/patologia , Inflamação/induzido quimicamente , Lipoproteínas VLDL/efeitos adversos , Macrófagos/metabolismo , Macrófagos/patologia , PPAR delta/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Ácidos Graxos/metabolismo , Células Espumosas/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Ligantes , Lipoproteínas VLDL/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , PPAR delta/agonistas , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/metabolismo
14.
Diabetes ; 60(5): 1446-57, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21471511

RESUMO

OBJECTIVE: Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis. RESEARCH DESIGN AND METHODS: Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor-deficient mice (Ldlr(-/-)) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis. RESULTS: In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal-related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr(-/-) mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid ß-oxidation. Nobiletin did not activate any peroxisome proliferator-activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus. CONCLUSIONS: Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.


Assuntos
Aterosclerose/tratamento farmacológico , Dieta/efeitos adversos , Dislipidemias/tratamento farmacológico , Flavonas/uso terapêutico , Resistência à Insulina/fisiologia , Lipoproteínas VLDL/metabolismo , Triglicerídeos/metabolismo , Animais , Aterosclerose/metabolismo , Butadienos/farmacologia , Dislipidemias/metabolismo , Eletroforese em Gel de Poliacrilamida , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , Insulina/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Receptor de Insulina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos
15.
Diabetes ; 58(10): 2198-210, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19592617

RESUMO

OBJECTIVE: The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance in vivo. RESEARCH DESIGN AND METHODS: LDL receptor-null (Ldlr(-/-)) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of insulin and glucose tolerance were determined. RESULTS: We report that naringenin treatment of Ldlr(-/-) mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha/PPARalpha-mediated transcription program; 2) prevented sterol regulatory element-binding protein 1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall insulin sensitivity and glucose tolerance. CONCLUSIONS: Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome.


Assuntos
Antiulcerosos/farmacologia , Glicemia/metabolismo , Dislipidemias/prevenção & controle , Antagonistas de Estrogênios/farmacologia , Flavanonas/farmacologia , Resistência à Insulina/fisiologia , Receptores de LDL/deficiência , Alanina Transaminase/sangue , Animais , Apolipoproteínas B/biossíntese , Apolipoproteínas B/efeitos dos fármacos , Apolipoproteínas B/metabolismo , Aspartato Aminotransferases/sangue , Peso Corporal , DNA Mitocondrial/genética , Gorduras na Dieta/farmacologia , Ingestão de Energia , Teste de Tolerância a Glucose , Insulina/sangue , Lipoproteínas VLDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triglicerídeos/metabolismo
16.
J Lipid Res ; 48(3): 699-708, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17130282

RESUMO

The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMG-CoA reductase inhibitor decreases cholesterol absorption and synthesis. In clinical trials, ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. The molecular mechanism for this enhanced efficacy has not been defined. Apolipoprotein B-100 (apoB-100) kinetics were determined in miniature pigs treated with ezetimibe (0.1 mg/kg/day), ezetimibe plus simvastatin (10 mg/kg/day), or placebo (n = 7/group). Ezetimibe decreased cholesterol absorption (-79%) and plasma phytosterols (-91%), which were not affected further by simvastatin. Ezetimibe increased plasma lathosterol (+65%), which was prevented by addition of simvastatin. The combination decreased total cholesterol (-35%) and LDL-cholesterol (-47%). VLDL apoB pool size decreased 26%, due to a 35% decrease in VLDL apoB production. LDL apoB pool size decreased 34% due to an 81% increase in the fractional catabolic rate, both of which were significantly greater than monotherapy. Combination treatment decreased hepatic microsomal cholesterol (-29%) and cholesteryl ester (-65%) and increased LDL receptor (LDLR) expression by 240%. The combination increased NPC1L1 expression in liver and intestine, consistent with increased SREBP2 expression. Ezetimibe plus simvastatin decreases VLDL and LDL apoB-100 concentrations through reduced VLDL production and upregulation of LDLR-mediated LDL clearance.


Assuntos
Apolipoproteína B-100/sangue , Azetidinas/farmacologia , Sinvastatina/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Ezetimiba , Feminino , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Lipoproteínas/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos
17.
Arterioscler Thromb Vasc Biol ; 25(12): 2608-14, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16210564

RESUMO

OBJECTIVE: Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), an enzyme in the cholesterol synthesis pathway, has the unique ability to inhibit cholesterol synthesis while simultaneously enhancing oxysterol synthesis. Our objectives were to determine, in vivo, if a novel OSC inhibitor reduced low-density lipoprotein (LDL) cholesterol and to define the mechanism(s) involved. METHODS AND RESULTS: Miniature pigs received the OSC inhibitor RO0717625 or placebo and a diet containing fat (34% of energy) and 400 mg per day of cholesterol. Treatment decreased plasma total cholesterol (-20%) and LDL cholesterol (-29%). Apolipoprotein B (apoB) kinetic parameters were determined. Very low-density lipoprotein (VLDL) apoB pool size decreased 22% because of inhibition of VLDL production (-43%). LDL apoB pool size decreased 22% because of a 1.5-fold increase in fractional catabolic rate (FCR). The increased FCR was associated with a 2-fold increase in hepatic LDL receptor mRNA. Hepatic total and microsomal cholesterol were reduced by 16% and 27%, respectively. Plasma lathosterol concentrations decreased 57%, reflecting inhibition of hepatic cholesterol synthesis. Treatment reduced plasma plant sterols and decreased postprandial cholesterol transport in chylomicrons. CONCLUSIONS: A novel OSC inhibitor, RO0717625, decreased VLDL and LDL apoB100 through decreased VLDL production and enhanced LDL clearance. Thus, OSC represents a potential therapeutic target for dyslipidemia.


Assuntos
Apolipoproteínas B/metabolismo , Colesterol/sangue , Inibidores Enzimáticos/farmacologia , Transferases Intramoleculares/antagonistas & inibidores , Fígado/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apolipoproteína B-100 , Apolipoproteínas B/biossíntese , Colesterol/biossíntese , HDL-Colesterol/biossíntese , HDL-Colesterol/sangue , LDL-Colesterol/biossíntese , LDL-Colesterol/sangue , VLDL-Colesterol/biossíntese , VLDL-Colesterol/sangue , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Fitosteróis/sangue , RNA Mensageiro/análise , Receptores de LDL/genética , Suínos , Porco Miniatura
18.
Trends Pharmacol Sci ; 26(7): 335-40, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15951028

RESUMO

The enzyme oxidosqualene:lanosterol cyclase (OSC) represents a novel target for the treatment of hypercholesterolemia. OSC catalyzes the cyclization of the linear 2,3-monoepoxysqualene to lanosterol, the initial four-ringed sterol intermediate in the cholesterol biosynthetic pathway. OSC also catalyzes the formation of 24(S),25-epoxycholesterol, a ligand activator of the liver X receptor. Inhibition of OSC reduces cholesterol biosynthesis and selectively enhances 24(S),25-epoxycholesterol synthesis. Through this dual mechanism, OSC inhibition decreases plasma levels of low-density lipoprotein (LDL)-cholesterol and prevents cholesterol deposition within macrophages. The recent crystallization of OSC identifies the mechanism of action for this complex enzyme, setting the stage for the design of OSC inhibitors with improved pharmacological properties for cholesterol lowering and treatment of atherosclerosis.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/biossíntese , Transferases Intramoleculares/química , Animais , Cristalização , Humanos , Transferases Intramoleculares/antagonistas & inibidores
19.
Biochim Biophys Acta ; 1738(1-3): 10-8, 2005 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-16427354

RESUMO

Previously, we have shown, in vivo, that the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor avasimibe decreases hepatic apolipoprotein (apo) B secretion into plasma. To test the hypothesis that avasimibe modulates postprandial triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg) containing retinol was given to 9 control miniature pigs and to 9 animals after 28 days treatment with avasimibe (10 mg/kg/day, n=5; 25 mg/kg/day, n=4). The kinetic parameters for plasma retinyl palmitate (RP) metabolism were determined by multi-compartmental modeling using SAAM II. Avasimibe decreased the 2-h TRL (d<1.006 g/mL; S(f)>20) triglyceride concentrations by 34%. The TRL triglyceride 0-12 h area under the curve (AUC) was decreased by 21%. In contrast, avasimibe had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma, however, the TRL RP 0-12 h AUC was decreased by 17%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate (FCR) was increased 1.4-fold with avasimibe. The TRL RP FCR was negatively correlated with very low density lipoprotein (VLDL) apoB production rate measured in the fasting state (r=-0.504). No significant changes in total intestinal lipid concentrations were observed. Thus, although avasimibe had no effect on intestinal TRL secretion, plasma TRL clearance was significantly increased; an effect that may relate to a decreased competition with hepatic VLDL for removal processes.


Assuntos
Acetatos/farmacologia , Inibidores Enzimáticos/farmacologia , Lipoproteínas/farmacocinética , Esterol O-Aciltransferase/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Triglicerídeos/farmacocinética , Acetamidas , Animais , Relação Dose-Resposta a Droga , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Cinética , Lipídeos/sangue , Lipoproteínas/sangue , Lipoproteínas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Taxa de Depuração Metabólica , Modelos Biológicos , Período Pós-Prandial , Sulfonamidas , Suínos , Porco Miniatura , Triglicerídeos/metabolismo
20.
J Lipid Res ; 44(5): 943-52, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12562847

RESUMO

Discovery of the ileal apical sodium-dependent bile acid transporter (ASBT) permitted development of specific inhibitors of bile acid reabsorption, potentially a new class of cholesterol-lowering agents. In the present study, we tested the hypothesis that combining the novel ASBT inhibitor, SC-435, with the HMG-CoA reductase inhibitor, atorvastatin, would potentiate reductions in LDL cholesterol (LDL-C) and LDL apolipoprotein B (apoB). ApoB kinetic studies were performed in miniature pigs fed a typical human diet and treated with the combination of SC-435 (5 mg/kg/day) plus atorvastatin (3 mg/kg/day) (SC-435+A) or a placebo. SC-435+A decreased plasma total cholesterol by 23% and LDL-C by 40%. Multicompartmental analysis (SAAM II) demonstrated that LDL apoB significantly decreased by 35% due primarily to a 45% increase in the LDL apoB fractional catabolic rate (FCR). SC-435+A significantly decreased hepatic concentrations of free cholesterol and cholesteryl ester, and increased hepatic LDL receptor mRNA consequent to increased cholesterol 7alpha-hydroxylase expression and activity. In comparison, SC-435 (10 mg/kg/day) monotherapy decreased LDL apoB by 10% due entirely to an 18% increase in LDL apoB FCR, whereas atorvastatin monotherapy (3 mg/kg/day) decreased LDL apoB by 30% due primarily to a 22% reduction in LDL apoB production. We conclude that SC-435+A potentiates the reduction of LDL-C and LDL apoB due to complementary mechanisms of action.


Assuntos
Apolipoproteínas B/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Ácidos Heptanoicos/farmacologia , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Transportadores de Ânions Orgânicos Dependentes de Sódio , Pirróis/farmacologia , Simportadores , Tropanos/farmacologia , Animais , Apolipoproteínas B/metabolismo , Atorvastatina , Proteínas de Transporte/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hidroximetilglutaril-CoA Redutases/metabolismo , Cinética , Lipoproteínas/sangue , Lipoproteínas/efeitos dos fármacos , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Porco Miniatura , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA