Chronic high-fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice.
Chronic high-fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice.
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肝脏特异性 ANGPTL4 基因敲除小鼠的长期高脂肪喂养和长时间禁食。
DOI：
10.1152/ajpendo.00144.2021
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Davies,BrandonSJ
中科院分区：
文献类型：
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作者：
Spitler,KathrynM;Shetty,ShwethaK;Cushing,EmilyM;Sylvers-Davie,KelliL;Davies,BrandonSJ
肥胖与血脂异常、异位脂质沉积和胰岛素抵抗有关。在小鼠中，血管生成素样蛋白 4 (ANGPTL4) 的整体或脂肪特异性功能丧失会导致血浆甘油三酯水平降低、脂肪甘油三酯摄取增加，并防止高脂饮食 (HFD) 引起的葡萄糖不耐受。 ANGPTL4 在肝脏中也高表达，但肝脏来源的 ANGPTL4 的作用尚不清楚。本研究的目的是确定肝细胞 ANGPTL4 在高脂肪饮食挑战期间对小鼠甘油三酯和葡萄糖稳态的贡献。我们生成了肝细胞特异性 ANGPTL4 缺陷 (Angptl4LivKO) 小鼠，给它们喂食 60% kcal/脂肪饮食 (HFD) 6 个月，并评估甘油三酯、肝脏和葡萄糖代谢表型。我们还探讨了长期禁食对 Angptl4LivKO 小鼠的影响。与对照小鼠相比，肝细胞来源的 ANGPTL4 的缺失不会导致甘油三酯分配或脂蛋白脂肪酶活性发生重大变化。有趣的是，虽然禁食 6 小时后空腹血浆甘油三酯水平没有差异，但禁食 18 小时后，正常食物喂养的 Angptl4LivKO 小鼠的甘油三酯水平低于对照小鼠。在 HFD 实验中，Angptl4LivKO 小鼠最初表现出葡萄糖耐量和胰岛素敏感性没有差异，但在 HFD 实验 6 个月后，这些小鼠的葡萄糖耐量出现改善。我们的数据表明，肝细胞 ANGPTL4 并不直接调节甘油三酯的分配，但肝源性 ANGPTL4 的缺失可能可以防止 HFD 诱导的葡萄糖不耐受，并影响长期禁食期间的血浆甘油三酯 (TG) 代谢。新和值得注意的 1) 肝细胞中血管生成素样 4 缺乏 (Angptl4LivKO) 不会改善高脂肪期间的甘油三酯表型2)Angptl4LivKO小鼠在长期高脂肪饮食后葡萄糖耐量得到改善。3)Angptl4LivKO小鼠在禁食18小时后空腹血浆甘油三酯水平降低，但禁食6小时后没有降低。
Obesity is associated with dyslipidemia, ectopic lipid deposition, and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet (HFD)–induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high-fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kcal/fat diet (HFD) for 6 mo and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting onAngptl4LivKOmice. The loss of hepatocyte-derived ANGPTL4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared with control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18-h fast, normal chow diet-fedAngptl4LivKOmice had lower triglyceride levels than control mice. On a HFD,Angptl4LivKOmice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6 mo on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma triglyceride (TG) metabolism during prolonged fasting.NEW & NOTEWORTHY1) Angiopoietin-like 4 deficiency in hepatocytes (Angptl4LivKO) does not improve triglyceride phenotypes during high-fat feeding.2)Angptl4LivKOmice have improved glucose tolerance after chronic high-fat diet.3)Angptl4LivKOmice have decreased fasting plasma triglyceride levels after an 18-h fast, but not after a 6-h fast.