RESUMO
AIM: Probucol is a controversial drug to inhibit ATP-binding cassette transporter A1 (ABCA1) and to exhibit some positive clinical effects such as regression of xanthomas. It reportedly rescues female infertility in scavenger receptor BI-deficient mice. Here, we investigated the effect of probucol on propagation in HDL-deficient mice as alternative models for impaired HDL-mediated cholesterol delivery. METHODS: Propagation of ABCA1-deficient (Abca1-/-) mice and lecithin: cholesterol acyltransferase (LCAT)-deficient (Lcat-/-) mice were quantitatively observed under the probucol treatment. RESULTS: Abca1-/- and Lcat-/- mice appear with negligible plasma HDL concentration. Upon backcrossing Abc1+/- with the Abc1-/- mice and cross-breeding between Abc1+/- mice, the numbers of Abc1-/- weaned pups were reduced to 54.7% and to 57.1% from those expected by Mendelian genetics, respectively. Similarly, Lcat-/- weaned pups decreased to 67.7% and to 35.9% but only in the male. Probucol severely reduced plasma HDL-cholesterol to 5% in the wild-type mice, but showed no effects on their propagation. Probucol corrected the deflections of the genotype distribution in the weaned pups recovery in the LCAT-deficient mice propagation but not in the ABCA1-deficient mice while plasma HDL was kept negligible. Probucol had no effect on cholesterol content in the steroidogenic organs of the HDL-deficient mice, while it somewhat increased plasma corticosterone and expression of adrenal cortex HMG-CoA reductase, StAR, cytochrome P450scc, and VKORC1 indicating increase in the synthesis of cholesterol and steroid hormones and in vitamin K turn-over. However, no evident mechanistic background was indicated. CONCLUSIONS: Probucol corrected deflection of genotype distribution in propagation of the LCAT-deficient mice but not the ABCA1-deficient mice at the weaning stage, apparently not through normalization of hypoalphalipoproteinemia.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/deficiência , HDL-Colesterol/sangue , Genótipo , Deficiência da Lecitina Colesterol Aciltransferase/genética , Probucol/farmacologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
We examined cholesterol homeostasis in mice with the two major cholesterol transport pathways for catabolism interrupted by disrupting abca1, lcat, or both. Plasma HDL markedly decreased in these genotype but LDL/VLDL decreased only in the double deficiency. Fractional catabolic rate of HDL increased in the order of wild typeAssuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo
, Colesterol/metabolismo
, Homeostase
, Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo
, Transportador 1 de Cassete de Ligação de ATP
, Animais
, Vasos Sanguíneos/efeitos dos fármacos
, Vasos Sanguíneos/metabolismo
, Vasos Sanguíneos/patologia
, Células Cultivadas
, Colesterol/genética
, Colesterol/farmacologia
, Ésteres do Colesterol/metabolismo
, Regulação da Expressão Gênica/efeitos dos fármacos
, Hepatócitos/efeitos dos fármacos
, Hepatócitos/enzimologia
, Homeostase/efeitos dos fármacos
, Lipoproteínas HDL/sangue
, Fígado/efeitos dos fármacos
, Fígado/metabolismo
, Camundongos
, Camundongos Endogâmicos C57BL
, Especificidade de Órgãos/efeitos dos fármacos
, RNA Mensageiro/genética
, RNA Mensageiro/metabolismo
, Esteroides/metabolismo