ApoJ as a novel hepatokine targeting muscle glucose metabolism

ApoJ 作为一种靶向肌肉葡萄糖代谢的新型肝因子

• 批准号: 9978058
• 负责人: YOUNG-BUM KIM
• 金额: $ 43.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978058
• 关键词: Area; Biological Process; Cell membrane; Communication; Complex; Coupled; Couples; Data; Diabetes Mellitus; Endocytosis; Fasting; Glucose Intolerance; Goals; Grant; Hepatic; Human; Impairment; Insulin; Insulin Receptor; Insulin Resistance; LDL-Receptor Related Protein 1; LDL-Receptor Related Protein 2; Lead; Link; Liver; LoxP-flanked allele; Maintenance; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathogenesis; Physiological; Physiology; Play; Proteins; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Skeletal Muscle; System; Technology; Tissues; Type 2 diabetic; blood glucose regulation; experimental study; glucose disposal; glucose metabolism; glucose transport; human subject; insulin regulation; insulin sensitivity; insulin sensitizing drugs; insulin signaling; interest; liver function; metabolic phenotype; new therapeutic target; novel; obesity treatment; receptor; sulfated glycoprotein 2

A major challenge in the field of metabolic physiology has been to understand the interorgan communication networks linking to glucose metabolism. One critical factor for this interorgan system is now known as hepatokines, identified from liver-derived proteins, and that play a pivotal role in regulating glucose metabolism and insulin sensitivity in skeletal muscle. ApoJ (apolipoprotienJ, also called clusterin) was not previously suspected to be involved in the regulation of glucose homeostasis and insulin signaling. Our preliminary data demonstrate that ApoJ may function as a hepatokine targeting insulin signaling and glucose metabolism in skeletal muscle, which could be mediated via the LRP1/2 (low-density lipoprotein receptor-related protein-1/2) signaling cascade. We thus hypothesize that the ApoJ → LRP1/2 axis is a novel metabolic signaling network that is crucial for the maintenance of normal glucose homeostasis and insulin signaling and that this couples with the insulin receptor system. The overall objective of this proposal is to identify ApoJ as a novel hepatokine that controls muscle glucose homeostasis via LRP1/2 signaling coupled with the insulin receptor system. Specifically, Aim1 will establish the biological function of ApoJ as a new hepatokine in glucose metabolism. Aim2 will determine whether the ApoJ → LRP1/2 signaling pathway is a key component of insulin action in skeletal muscle. Aim3 will elucidate the cellular mechanisms for the insulin-sensitizing effects of ApoJ. To accomplish these aims, we will use state-of-the-art technologies, including a conditional floxed ApoJ, LRP1 and LRP2 models as well as human subjects to clarify the metabolic function of the ApoJ → LRP2 axis in the context of interorgan communication networks. These studies provide a unique opportunity to establish a new paradigm in which the ApoJ → LRP2 signaling network is a key determinant of glucose homeostasis, and may offer a novel target for the treatment of obesity and diabetes.

代谢生理学领域的一个主要挑战是理解器官间的关系

项目成果

Urine clusterin/apolipoprotein J is linked to tubular damage and renal outcomes in patients with type 2 diabetes mellitus.

• DOI: 10.1111/cen.13360
• 发表时间: 2017-08
• 期刊: Clinical endocrinology
• 影响因子: 3.2
• 作者: Kim SS;Song SH;Kim JH;Jeon YK;Kim BH;Kang MC;Chun SW;Hong SH;Chung M;Kim YK;Kim IJ;Kim YB
• 通讯作者: Kim YB

TET2: Is a potential gatekeeper for the action of thiazolidinedione in fat cells?

TET2：噻唑烷二酮在脂肪细胞中的作用是否是潜在的看门人？

• DOI: 10.1016/j.metabol.2018.10.001
• 发表时间: 2018
• 期刊: Metabolism: clinical and experimental
• 作者: Seo,JiA;Kim,Young-Bum
• 通讯作者: Kim,Young-Bum