Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice.
Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice.
复制标题
肝 FoxO 缺失引起的胰岛素敏化不足以降低小鼠的动脉粥样硬化。
DOI：
10.1101/2023.10.14.562366
复制
发表时间：
2023
期刊：
影响因子：
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通讯作者：
Haeusler,RebeccaA
中科院分区：
文献类型：
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作者：
Izquierdo,MaríaConcepción;Harris,Michael;Shanmugarajah,Niroshan;Zhong,Kendra;Ozcan,Lale;Fredman,Gabrielle;Haeusler,RebeccaA
背景2型糖尿病与动脉粥样硬化性心血管疾病的风险增加有关。有人认为，胰岛素抵抗是这种联系的基础，可能是通过改变动脉壁细胞的功能。我们的目的是测试是否提高全身胰岛素敏感性降低atherosclerosis.MethodsWe使用的小鼠，建立有改善全身胰岛素敏感性：那些缺乏FoxO转录因子的肝细胞。三种肝脏FoxO同种型（FoxO 1、FoxO 3和FoxO 4）共同起作用以促进肝脏葡萄糖输出，消融它们可降低葡萄糖产生，降低循环葡萄糖和胰岛素，并改善全身胰岛素敏感性。我们使这些小鼠易受动脉粥样硬化在两种不同的方式，通过注射功能获得性AAV8.mPcsk9D377Y和通过与Ldlr−/− mice.ResultsWe交叉验证，肝FoxO消融改善全身胰岛素敏感性在这些动脉粥样硬化设置。我们观察到FoxO缺乏并没有减少动脉粥样硬化，在某些情况下反而增加了动脉粥样硬化。这些表型与FoxO-消融mice.ConclusionsThese研究结果表明，全身胰岛素增敏不足以减少动脉粥样硬化循环甘油三酯的大量增加相吻合。
BackgroundType 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis.MethodsWe used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9D377Y and by crossing with Ldlr−/− mice.ResultsWe verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice.ConclusionsThese findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis.