University of Patras, School of Medicine, Department of Pharmacology, Rio, Achaias, TK. 26500, Greece.
Fondazione Policlinico Universitario A.Gemelli IRCSS, Rome, Italy; Istituto di Fisica, Università Cattolica del Sacro Cuore Roma, Italy.
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1351-1360. doi: 10.1016/j.bbadis.2019.02.003. Epub 2019 Feb 10.
High density lipoprotein (HDL) has attracted the attention of biomedical community due to its well-documented role in atheroprotection. HDL has also been recently implicated in the regulation of islets of Langerhans secretory function and in the etiology of peripheral insulin sensitivity. Indeed, data from numerous studies strongly indicate that the functions of pancreatic β-cells, skeletal muscles and adipose tissue could benefit from improved HDL functionality. To better understand how changes in HDL structure may affect diet-induced obesity and type 2 diabetes we aimed at investigating the impact of Apoa1 or Lcat deficiency, two key proteins of peripheral HDL metabolic pathway, on these pathological conditions in mouse models. We report that universal deletion of apoa1 or lcat expression in mice fed western-type diet results in increased sensitivity to body-weight gain compared to control C57BL/6 group. These changes in mouse genome correlate with discrete effects on white adipose tissue (WAT) metabolic activation and plasma glucose homeostasis. Apoa1-deficiency results in reduced WAT mitochondrial non-shivering thermogenesis. Lcat-deficiency causes a concerted reduction in both WAT oxidative phosphorylation and non-shivering thermogenesis, rendering lcat mice the most sensitive to weight gain out of the three strains tested, followed by apoa1 mice. Nevertheless, only apoa1 mice show disturbed plasma glucose homeostasis due to dysfunctional glucose-stimulated insulin secretion in pancreatic β-islets and insulin resistant skeletal muscles. Our analyses show that both apoa1 and lcat mice fed high-fat diet have no measurable Apoa1 levels in their plasma, suggesting no direct involvement of Apoa1 in the observed phenotypic differences among groups.
高密度脂蛋白（HDL）因其在动脉粥样保护中的作用已被充分证实而引起了生物医学界的关注。最近的研究表明，HDL 还参与胰岛朗格汉斯细胞分泌功能的调节以及外周胰岛素敏感性的发生。事实上，大量研究数据强烈表明，胰腺β细胞、骨骼肌和脂肪组织的功能可以受益于改善 HDL 的功能。为了更好地了解 HDL 结构的变化如何影响饮食诱导的肥胖和 2 型糖尿病，我们旨在研究载脂蛋白 A1（Apoa1）或卵磷脂胆固醇酰基转移酶（Lcat）缺乏这两种外周 HDL 代谢途径的关键蛋白对这些病理条件的影响。我们报告称，在喂食西式饮食的小鼠中，普遍缺失 Apoa1 或 Lcat 表达，与 C57BL/6 对照组相比，会导致对体重增加的敏感性增加。这些在小鼠基因组中的变化与白色脂肪组织（WAT）代谢激活和血浆葡萄糖稳态的离散影响相关。Apoa1 缺乏导致 WAT 线粒体非颤抖性产热减少。Lcat 缺乏导致 WAT 氧化磷酸化和非颤抖性产热协同减少，使得 lcat 小鼠成为三种测试品系中对体重增加最敏感的，其次是 apoa1 小鼠。然而，只有 apoa1 小鼠由于胰腺β细胞中葡萄糖刺激胰岛素分泌功能障碍和骨骼肌胰岛素抵抗而出现血浆葡萄糖稳态紊乱。我们的分析表明，喂食高脂肪饮食的 apoa1 和 lcat 小鼠的血浆中均无法检测到 Apoa1 水平，这表明 Apoa1 并未直接参与各组之间观察到的表型差异。
