RESUMO
Obese and diabetic humans display decreased plasma high-density lipoprotein cholesterol (HDL-C) concentrations and an increased risk for coronary heart disease. However, investigation on HDL metabolism in obesity with a particular emphasis on hepatic ATP-binding cassette transporter A1 (ABCA1), the primary factor for HDL formation, has not been well studied. Human apolipoprotein B(100) transgenic (hApoB(tg)) and brown adipose tissue deficient (BATless) mice were crossed to generate hApoB(tg)/BATless mice. Male and female hApoB(tg) and hApoB(tg)/BATless mice were maintained on either a regular rodent chow diet or a diet high in fat and cholesterol until 24 weeks of age. The hApoB(tg)/BATless mice that were fed a HF/HC diet became obese, developed hepatic steatosis, and had significantly elevated plasma insulin levels compared with their hApoB(tg) counterparts, but plasma concentrations of total cholesterol, HDL-C, triglycerides, and free fatty acids and lipoprotein distribution between genotypes were not significantly different. Hepatic expression of genes encoding HDL-modifying factors (e.g., scavenger receptor, class B, type I, hepatic lipase, lecithin:cholesterol acyltransferase, and phospholipid transfer protein) was either altered significantly or showed a trend of difference between 2 genotypes of mice. Importantly, hepatic protein levels of ABCA1 were significantly lowered by â¼35% in male obese hApoB(tg)/BATless mice with no difference in mRNA levels compared with hApoB(tg) counterparts. Despite reduced hepatic ABCA1 protein levels, plasma HDL-C concentrations were not altered in male obese hApoB(tg)/BATless mice. The result suggests that hepatic ABCA1 may not be a primary contributing factor for perturbations in HDL metabolism in obesity-induced hyperinsulinemia.
Assuntos
Tecido Adiposo Marrom/metabolismo , Apolipoproteína B-100/metabolismo , Hiperinsulinismo/metabolismo , Lipoproteínas HDL/metabolismo , Obesidade/complicações , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apolipoproteína B-100/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/etiologia , Insulina/sangue , Lipídeos/sangue , Lipoproteínas HDL/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Obesidade/metabolismoRESUMO
Cell division is inherently mechanical, with cell mechanics being a critical determinant governing the cell shape changes that accompany progression through the cell cycle. The mechanical properties of symmetrically dividing mitotic cells have been well characterized, whereas the contribution of cellular mechanics to the strikingly asymmetric divisions of female meiosis is very poorly understood. Progression of the mammalian oocyte through meiosis involves remodeling of the cortex and proper orientation of the meiotic spindle, and thus we hypothesized that cortical tension and stiffness would change through meiotic maturation and fertilization to facilitate and/or direct cellular remodeling. This work shows that tension in mouse oocytes drops about sixfold during meiotic maturation from prophase I to metaphase II and then increases â¼1.6-fold upon fertilization. The metaphase II egg is polarized, with tension differing â¼2.5-fold between the cortex over the meiotic spindle and the opposite cortex, suggesting that meiotic maturation is accompanied by assembly of a cortical domain with stiffer mechanics as part of the process to achieve asymmetric cytokinesis. We further demonstrate that actin, myosin-II, and the ERM (Ezrin/Radixin/Moesin) family of proteins are enriched in complementary cortical domains and mediate cellular mechanics in mammalian eggs. Manipulation of actin, myosin-II, and ERM function alters tension levels and also is associated with dramatic spindle abnormalities with completion of meiosis II after fertilization. Thus, myosin-II and ERM proteins modulate mechanical properties in oocytes, contributing to cell polarity and to completion of meiosis.