Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.
Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.
J Lipid Res. 2022 Dec;63(12):100296. doi: 10.1016/j.jlr.2022.100296. Epub 2022 Oct 13.
Dennd5b plays a pivotal role in intestinal absorption of dietary lipids in mice and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism in mice. Hypercholesterolemia was induced in Dennd5b mice by infection with an adeno-associated virus expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, and then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b mice, Dennd5b mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis quantified by en face analysis and in aortic root sections, revealed significantly smaller lesions in Dennd5b compared to Dennd5b mice. Additionally, Dennd5b mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to Dennd5b mice. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b.
Dennd5b 在小鼠肠道对膳食脂质的吸收中发挥关键作用，并且与人类的体重指数相关。本研究旨在探讨全身性 Dennd5b 缺失对小鼠血浆脂质浓度、动脉粥样硬化和肝脏脂质代谢的影响。通过感染表达前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9 丝氨酸蛋白酶（PCSK9）功能获得性突变（PCSK9D377Y）的腺相关病毒并给予西方饮食喂养 12 周，诱导 Dennd5b 小鼠发生高胆固醇血症。在 12 周的时间里，监测体重和血浆脂质浓度，然后定量分析主动脉粥样硬化和肝脏脂质含量。与 Dennd5b 小鼠相比，Dennd5b 小鼠对饮食诱导的体重增加和 PCSK9 诱导的高胆固醇血症具有抗性。通过正面分析和主动脉根部切片定量分析动脉粥样硬化，发现 Dennd5b 小鼠的病变明显小于 Dennd5b 小鼠。此外，Dennd5b 小鼠的肝脏脂质含量（甘油三酯和胆固醇）明显低于 Dennd5b 小鼠。为了深入了解肝脏脂质减少的基础，我们使用定量 PCR 测量了参与肝脏脂质代谢的基因的 mRNA 丰度。Dennd5b 肝脏中涉及肝脏脂质代谢和脂质储存的关键基因的表达水平存在差异，包括 Pparg、Cd36 和 Pnpla3。这些发现表明 Dennd5b 在缺乏 Dennd5b 的情况下对血浆和肝脏脂质浓度具有显著影响，并对 PCSK9 诱导的高胆固醇血症具有抗性。
