The characterization of Cela2a, a novel disease gene for metabolic syndrome in health and diseases

调节胰岛素抵抗及其进展为2型糖尿病(T2D)的分子机制尚不清楚 了解并可能揭示减轻T2D负担的治疗机会。我们最近确认了 CELA2A基因功能丧失突变(Esteghamat&Mani，NAT.吉内。2019年)，其中 在具有极端表型的家系中编码胰腺弹性蛋白酶类糜蛋白酶样弹性蛋白酶2A 代谢综合征、2型糖尿病和早发性动脉粥样硬化。有趣的是，全基因组 关联性研究也表明CELA2A基因的常见变异与 血压、低密度脂蛋白胆固醇和体重指数，强调了它在普通人群疾病中的作用。 虽然我们只知道它是一种胰腺外分泌酶，但我们发现它是一种循环蛋白。 它在胰腺外组织中表达，包括肠道。它的血浆水平在每顿饭后同步上升 对健康人血浆胰岛素水平的影响。我们对CELA2A功能的描述揭示了它有能力 触发胰岛素分泌和敏感性。相比之下，在中国发现的催化非活性突变CELA2A蛋白 该队列增加了血小板聚集，降低了胰岛素敏感性。从机制上讲，CELA2A被发现 蛋白水解性切割PAR2等GPCRs并诱导依赖PAR2的AMPK激活，而突变 CELA2As触发不同的PAR2依赖通路，导致ERK增加和AMPK减少 激活。因此，CELA2A似乎是PAR2的内源性配体，GPCR参与了 葡萄糖稳态的调节。这些功能强调了CELA2A作为一种新的风险因素和 是治疗T2D的有吸引力的治疗靶点。我们将研究它的生理功能。 CELA2A及其在全球、腺泡细胞和腺泡细胞葡萄糖稳态中作用的分子机制 肠道特异的Cela2a基因敲除小鼠，具有焦点PAR2依赖的通路。Cela2a KO小鼠是理想的 这一目标表明，胰岛素敏感性受损，肝脏和血浆甘油三酯增加相匹配 人类的表型。

Molecular mechanisms that regulate insulin resistance and its progression to type2 diabetes (T2D) are not understood and might reveal a therapeutic opportunity to reduce the burden of T2D. We recently identified causative loss-of-function mutations in the CELA2A gene (Esteghamat & Mani, Nat. Genet. 2019), which encodes the pancreatic elastase Chymotrypsin-like ELAstase 2A in kindreds with extreme phenotypes of metabolic syndrome, type 2 diabetes, and early-onset atherosclerosis. Interestingly, the genome-wide association studies have also shown a strong association between common variants in the CELA2A gene and blood pressure, LDL cholesterol and BMI, underscoring its role in the disease of the general population. Although only known for its function as a pancreatic exocrine enzyme, we found it to be a circulating protein that is expressed in the extrapancreatic tissues, including gut. Its plasma levels rise after each meal in parallel to plasma insulin levels in healthy humans. Our characterization of CELA2A functions revealed its ability to trigger insulin secretion and sensitivity. In contrast, the catalytically inactive mutant CELA2A proteins found in the cohort increased platelet aggregation and reduced insulin sensitivity. Mechanistically, CELA2A was found to proteolytically cleave GPCRs such as PAR2 and induce PAR2-dependent activation of AMPK, while mutant CELA2As trigger different PAR2-dependent pathways, resulting in increased ERK and reduced AMPK activation. Thus, CELA2A appears to be an endogenous ligand of PAR2, a GPCR that has been implicated in the regulation of glucose homeostasis. These functions underscore CELA2A’s role as a novel risk factor and an attractive therapeutic target for the treatment of T2D. We will investigate the physiological functions of CELA2A and explore its molecular mechanisms of action in glucose homeostasis in global, acinar cell- and gut-specific Cela2a knockout mice, with a focus PAR2-dependent pathways. Cela2a KO mice are ideal for this goal as they show impaired insulin sensitivity and increased hepatic and plasma triglycerides that match the phenotypes of humans.