Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes
Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes
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可溶性 Klotho 改善 2 型糖尿病的肝葡萄糖和脂质稳态
DOI：
10.1016/j.omtm.2020.08.002
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发表时间：
2020-09-11
影响因子：
4.7
通讯作者：
Zheng, Lu
中科院分区：
文献类型：
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作者：
Gu, Huiying;Jiang, Wei;Zheng, Lu
2型糖尿病（Type 2 Diabetes，T2 D）是全球范围内发病率最高的代谢性疾病之一，与胰岛素抵抗（Insulin Resistance，IR）及合并非酒精性脂肪性肝病（Nonalcoholic Fatty Liver Disease，NAFLD）的风险密切相关。以前的研究表明，可溶性klotho（sKL）可以作为一种循环激素，介导能量代谢，但详细的机制知之甚少。在这项研究中，我们建立了野生型（WT）、sKL杂合型（Kr+/-）和sKL转基因（TgKL）小鼠的T2 D模型，这些小鼠连续饲喂高脂饮食（HFD），并构建了稳定过表达sKL的L02细胞系，以研究sKL对肝脏葡萄糖和脂质代谢的影响。令人惊讶的是，我们发现sKL缺乏导致HFD喂养的KL+/-糖尿病小鼠的糖尿病表型和肝脏糖脂代谢紊乱加重（Kr+/- DM），而TgKL糖尿病小鼠（TgKL DM）表现出改善的糖尿病表型和降低的IR。体外和体内机制研究表明，sKL可以抑制PI 3 K/AKT/mTORC 1信号，上调过氧化物酶体增殖物激活受体a（PPARa）的表达，通过直接与HFD喂养的T2 D小鼠中的1型胰岛素样生长因子受体（IGF 1 R）相互作用。因此，sKL可以改善肝脏糖脂稳态，以改善糖尿病表型和脂质蓄积，并可能作为治疗T2 D和降低NAFLD风险的潜在治疗靶点。
Type 2 diabetes (T2D) is one of the most escalating global metabolic diseases, which is highly associated with insulin resistance (IR) and risk of combination with nonalcoholic fatty liver disease (NAFLD). Previous studies suggest that soluble klotho (sKL) could serve as a circulating hormone to mediate energy metabolism, but the detailed mechanism is poorly understood. In this study, we generated T2D models of wild-type (WT), sKL heterozygous (Kr+/-), and sKL transgenic (TgKL) mice continuously fed a high-fat diet (HFD) and constructed L02 cell lines that stably overexpress sKL to investigate the effect of sKL on hepatic glucose and lipid metabolism. Surprisingly, we discovered that sKL deficiency resulted in exacerbated diabetic phenotypes and hepatic glucolipid metabolism disorders in HFD-fed KL+/- diabetic mice (Kr+/- DM), whereas TgKL diabetic mice (TgKL DM) exhibited ameliorated diabetic phenotypes and decreased IR. Mechanistic studies in vitro and in vivo demonstrated that sKL could inhibit the PI3K/AKT/mTORC1 signaling to upregulate peroxisome proliferator-activated receptor a (PPARa) expression by directly interacting with type 1 insulin-like growth factor receptor (IGF1R) in HFD-fed T2D mice. Thus, sKL could improve hepatic glucolipid homeostasis to ameliorate diabetic phenotypes and lipid accumulation and may function as a potential therapeutic target for the treatment of T2D and reduce the risk of NAFLD.