反义寡核苷酸 Angptl8 可改善脂肪组织脂质代谢，预防啮齿类动物饮食诱导的非酒精性脂肪性肝病和肝胰岛素抵抗。
Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents.
机构信息
Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, New Haven, CT, 06520, USA.
Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06520, USA.
出版信息
Diabetologia. 2018 Jun;61(6):1435-1446. doi: 10.1007/s00125-018-4579-1. Epub 2018 Mar 1.
AIMS/HYPOTHESIS: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake.
METHODS
ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry.
RESULTS
Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice.
CONCLUSIONS/INTERPRETATION: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.
目的/假设：靶向脂肪组织脂蛋白脂肪酶的调节剂可以增强脂肪脂质清除，防止异位脂质积累，从而改善胰岛素抵抗和 2 型糖尿病。血管生成素样蛋白 8 (ANGPTL8) 是一种胰岛素调节的脂蛋白脂肪酶抑制剂，在小鼠脂肪组织中强烈表达。然而，Angptl8 基因敲除小鼠并没有改善胰岛素抵抗。我们假设，在高脂肪喂养的成年啮齿动物中，使用第二代针对 Angptl8 的反义寡核苷酸 (ASO) 进行药理学抑制，通过促进脂肪脂质摄取来预防异位脂质积累和胰岛素抵抗。
方法
通过定量 PCR 评估肥胖症患者剖腹手术中网膜脂肪组织的 ANGPTL8 表达。用 ASO 处理高脂肪喂养的 Sprague Dawley 大鼠和 C57BL/6 小鼠，并通过大鼠高胰岛素-正葡萄糖钳夹试验和小鼠葡萄糖耐量试验评估胰岛素敏感性。评估介导脂质诱导的肝胰岛素抵抗的因素，包括脂质含量、蛋白激酶 Cε (PKCε) 激活和胰岛素刺激的 Akt 磷酸化。通过混合餐耐量试验评估大鼠脂肪脂质摄取。通过间接测热法评估小鼠能量平衡。
结果
与 BMI 匹配的胰岛素敏感个体相比，患有脂肪肝和胰岛素抵抗的肥胖个体网膜脂肪 ANGPTL8 mRNA 表达更高。Angptl8 ASO 可预防高脂肪喂养大鼠的肝脂肪变性、PKCε 激活和肝胰岛素抵抗。Angptl8 ASO 处理的大鼠白色脂肪组织中的餐后三酰甘油摄取增加。Angptl8 ASO 可保护高脂肪喂养的小鼠免受葡萄糖不耐受。尽管净能量平衡没有变化，但 Angptl8 ASO 增加了高脂肪喂养小鼠的脂肪量。
结论/解释：抑制脂肪组织脂蛋白脂肪酶是一种增强脂肪脂质摄取的新治疗方法，可用于治疗非酒精性脂肪性肝病和胰岛素抵抗。与此一致，脂肪组织 ANGPTL8 是这些疾病的候选治疗靶点。
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