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1.
J Lipid Res ; 63(3): 100174, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35101425

RESUMO

Antisense oligonucleotides (ASOs) against Ldl receptor (Ldlr-ASO) represent a promising strategy to promote hypercholesterolemic atherosclerosis in animal models without the need for complex breeding strategies. Here, we sought to characterize and contrast atherosclerosis in mice given Ldlr-ASO with those bearing genetic Ldlr deficiency. To promote atherosclerosis, male and female C57Bl6/J mice were either given weekly injections of Ldlr-ASO (5 mg/kg once per week) or genetically deficient in Ldlr (Ldlr-/-). Mice consumed either standard rodent chow or a diet high in saturated fat and sucrose with 0.15% added cholesterol for 16 weeks. While both models of Ldlr deficiency promoted hypercholesterolemia, Ldlr-/- mice exhibited nearly 2-fold higher cholesterol levels than Ldlr-ASO mice, reflected by increased VLDL and LDL levels. Consistent with this, the en face atherosclerotic lesion area was 3-fold and 3.6-fold greater in male and female mice with genetic Ldlr deficiency, respectively, as compared with the modest atherosclerosis observed following Ldlr-ASO treatment. Aortic sinus lesion sizes, fibrosis, smooth muscle actin, and necrotic core areas were also larger in Ldlr-/- mice, suggesting a more advanced phenotype. Despite a more modest effect on hypercholesterolemia, Ldlr-ASO induced greater hepatic inflammatory gene expression, macrophage accumulation, and histological lobular inflammation than was observed in Ldlr-/- mice. We conclude Ldlr-ASO is a promising tool for the generation of complex rodent models with which to study atherosclerosis but does not promote comparable levels of hypercholesterolemia or atherosclerosis as Ldlr-/- mice and increases hepatic inflammation. Thus, genetic Ldlr deficiency may be a superior model, depending on the proposed use.


Assuntos
Aterosclerose , Hipercolesterolemia , Animais , Aterosclerose/metabolismo , Colesterol , Modelos Animais de Doenças , Feminino , Hipercolesterolemia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Preparações Farmacêuticas , Receptores de LDL/genética
3.
Endocrinology ; 158(9): 2848-2859, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28651330

RESUMO

Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a dietary fatty acid that promotes weight loss and disproportionate fat loss. Obese mice fed a high-fat, high-sucrose (HFHS) diet containing 10,12 CLA are resistant to weight gain and contain markedly reduced subcutaneous fat and adiponectin, with a concurrent lack of improvement in insulin sensitivity despite significant weight loss. Taken together, 10,12 CLA promotes a phenotype resembling peroxisome proliferator-activated receptor (PPAR)γ antagonism. Because thiazolidinediones such as rosiglitazone (Rosi) are used clinically to improve insulin sensitivity by activating PPARγ, with particular efficacy in subcutaneous white adipose tissue, we hypothesized that Rosi would improve glucose metabolism in mice losing weight with 10,12 CLA. Obese low-density lipoprotein receptor-deficient mice were fed a HFHS control diet, or supplemented with 1% 10,12 CLA with or without Rosi (10 mg/kg) for 8 weeks. Body composition, glucose and insulin tolerance tests, tissue gene expression, and plasma lipid analyses were performed. Mice consuming 10,12 CLA with Rosi lost weight and body fat compared with control groups, but with a healthier redistribution of body fat toward more subcutaneous adipose tissue than with 10,12 CLA alone. Further, Rosi improved 10,12 CLA-mediated insulin resistance parameters and increased plasma and subcutaneous adipose tissue adiponectin levels without adverse effects on plasma or hepatic lipids. We conclude that cotreatment of mice with 10,12 CLA and Rosi promotes fat loss with a healthier fat distribution that leads to improved insulin sensitivity, suggesting that the combination treatment strategy of 10,12 CLA with Rosi could have therapeutic potential for obesity treatment.


Assuntos
Resistência à Insulina , Ácidos Linoleicos Conjugados/farmacologia , Síndrome Metabólica/metabolismo , Tiazolidinedionas/farmacologia , Células 3T3-L1 , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Modelos Animais de Doenças , Glucose/metabolismo , Ácidos Linoleicos Conjugados/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Receptores de LDL/genética , Rosiglitazona , Tiazolidinedionas/administração & dosagem
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