KLF15在代谢调节中的研究进展
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1.1)沈阳体育学院运动健康学院,沈阳 110115;2.2)上海体育学院运动科学学院,上海 200438;3.3)沈阳体育学院运动与健康研究中心,沈阳 110115

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国家自然科学基金


Research progress of KLF15 in metabolic regulation
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1.1)School of Sports and Health, Shenyang Sport University, Shenyang 110115, China;2.2)School of Sports and Human Sciences, Shanghai Sport University, Shanghai 200438, China;3.3)Exercise and Health Research Center/Department of Kinesiology, Shenyang Sport University, Shenyang 110115, China

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The National Natural Science Foundation of China

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    摘要:

    伴随人类生活方式改变,代谢紊乱导致的肥胖、2型糖尿病、非酒精性脂肪肝等慢性病已成为严重威胁人类健康的公共卫生问题。KLF15是高度保守的KLF家族成员之一,在多个代谢活跃器官均有表达,具有广泛的调节作用。近年来,大量研究表明KLF15在脂肪、骨骼肌、肝脏中调节糖、脂、氨基酸代谢,并与营养物质的获取、转运、利用密切相关。本文重点阐述了了KLF15在这代谢调节作用及其作用机制,有助于更好的了解KLF15在代谢领域的调节作用,希望为治疗代谢相关疾病提供新的视角并推进精准医学。

    Abstract:

    With changes in human lifestyle, chronic diseases caused by metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, have become serious public health issues threatening human health. These diseases not only significantly increase the disease burden on humans but also put immense pressure on global healthcare systems. Therefore, understanding and exploring the molecular mechanisms leading to these diseases, especially the role of metabolic regulators, is crucial for developing effective prevention and treatment strategies. KLF15, one of the highly conserved members of the KLF family, has gained widespread attention due to its expression and regulatory roles in various metabolically active organs. Recent studies have shown that KLF15 regulates glucose, lipid, and amino acid metabolism in adipose tissue, skeletal muscle, and liver, and is closely related to the acquisition, transport, and utilization of nutrients. The role of KLF15 in glucose metabolism is primarily reflected in its regulation of gluconeogenesis and glucose uptake. KLF15 influences blood glucose levels by regulating the expression of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Research has shown that KLF15 knockout (KO) mice exhibit severe hypoglycemia and reduced liver glycogen content after 18 hours of fasting. Additionally, KLF15 interacts with muscle enhancer factor 2 (MEF2A) to activate the GLUT4 promoter, significantly enhancing glucose uptake in skeletal muscle and adipose tissue. In insulin-resistant individuals, KLF15 expression is reduced, affecting insulin sensitivity by regulating genes related to lipid metabolism and mitochondrial function. In terms of lipid metabolism, KLF15 expression significantly increases during adipocyte differentiation, regulating the expression of genes such as C/EBPβ, C/EBPδ, and PPARγ. KLF15 KO mice show reduced lipogenesis and increased lipolysis, highlighting its importance in fat storage and energy balance. In brown adipose tissue (BAT), KLF15 regulates genes involved in lipid uptake and thermogenesis, such as CD36, Slc25a20, and Cpt1a. KLF15 KO mice fail to maintain body temperature during fasting-induced cold exposure, demonstrating the critical role of KLF15 in BAT metabolism and energy balance. Specifically, KLF15 forms positive feedback loops with adipogenic transcription factors such as GR, PPARγ, and C/EBP, promoting adipocyte differentiation and maturation. In BAT, KLF15 is crucial not only for regulating lipid uptake but also for promoting non-shivering thermogenesis by regulating thermogenic genes, thereby helping to maintain body temperature in cold environments. In protein metabolism, KLF15 regulates key enzymes involved in branched-chain amino acid (BCAA) metabolism, such as BCAT2 and ALT, which are essential for gluconeogenesis and maintaining blood glucose levels. KLF15 KO mice show reduced expression of these enzymes, leading to impaired amino acid catabolism. KLF15 regulates muscle protein synthesis and degradation through the mTOR pathway and E3 ubiquitin ligases (e.g., atrogin-1 and MuRF1), indicating its significance in muscle protein metabolism and stress response, especially in glucocorticoid-induced muscle atrophy. Studies have shown that KLF15 expression in muscle tissue is regulated by the glucocorticoid receptor (GR). Glucocorticoids regulate KLF15 expression through GR, which in turn affects the mTOR signaling pathway, inhibiting protein synthesis and promoting protein degradation. This mechanism is particularly significant in glucocorticoid-induced muscle atrophy.KLF15 also responds significantly to exercise, particularly acute endurance exercise and long-term aerobic training. Acute endurance exercise increases KLF15 expression in muscle and adipose tissue, enhancing lipid synthesis and protein catabolism. In contrast, chronic exercise reduces KLF15 expression, improving insulin sensitivity and mitigating diabetes-induced myopathy. However, further research is needed to explore the effects of different forms of exercise on KLF15 and its specific roles in various tissues. In conclusion, KLF15 plays a crucial role in maintaining overall metabolic balance. It regulates glucose, lipid, amino acid, and protein metabolism, responding to nutritional status and exercise to maintain energy homeostasis. The role of KLF15 in glucose metabolism involves regulating gluconeogenesis and glucose uptake, in lipid metabolism through regulating fat synthesis and breakdown, and in protein metabolism through influencing branched-chain amino acid metabolism and muscle protein synthesis and degradation. Future research should continue to delve into the specific mechanisms of KLF15 in different metabolic pathways, especially its regulatory roles under various exercise forms and nutritional states, to provide new perspectives and theoretical foundations for treating metabolic diseases.(Graphic Abstract)

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衣雪洁,李梦焕,杨旸,万根萌,段子强,常波. KLF15在代谢调节中的研究进展[J].生物化学与生物物理进展,,():

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  • 收稿日期:2024-03-15
  • 最后修改日期:2024-07-02
  • 接受日期:2024-07-02
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