A causal role of the carboxylic acid transporter SLC16A11 in the pathogenesis of type 2 diabetes?

羧酸转运蛋白 SLC16A11 在 2 型糖尿病发病机制中的因果作用？

• 批准号: 421530519
• 负责人: Professor Dr. Andreas L. Birkenfeld
• 金额: --
• 依托单位: Innere Medizin IV: Endokrinologie und Diabetologie, Angiologie, Nephrologie und Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/421530519?language=en
• 关键词: causal; role; carboxylic; acid; transporter

Type 2 diabetes is an epidemically growing health threat all over the world. Despite modern therapies, diabetes associated mortality is 2-3 times higher compared to non-affected individuals. Therefore, a deeper understanding and more efficient therapies are an urgent clinical need. The SLC16A11 gene, which encodes a plasma-membrane transporter for monocarboxylates such as pyruvate and lactate, shows a strong association with the development of type 2 diabetes in genome-wide association studies in patients. Specifically, a haplotype in the gene leads to reduced expression of SLC16A11 and type 2 diabetes. The knockdown of SLC16A11 in primary hepatocytes results in the accumulation of triglycerides and diacylglycerols, mediators of insulin resistance. Conversely, our own studies show that de novo lipogenesis is significantly reduced in human SLC16A11-overexpressing HEK cells. However, it is not yet known how SLC16A11 is associated with altered lipid metabolism and which biochemical, cellular and physiological mechanisms lead to type 2 diabetes when SLC16A11 function is disturbed. In preliminary studies, we were able to demonstrate that SLC16A11 is strongly expressed in human and murine liver, and that hepatic mRNA expression is significantly reduced in the presence of NALFD, insulin resistance and T2D in mice and patients. These data support the idea that SLC16A11 is associated with the development of non-alcoholic fatty liver disease and insulin resistance, and thus, type 2 diabetes. Therefore, we hypothesize that SLC16A11 contributes to the development of non-alcoholic fatty liver disease and insulin resistance by affecting the transport of monocarboxylates such as lactate and pyruvate, which serve as substrates for lipid metabolism and thus reduce insulin sensitivity. With this proposal, we aim at determining the substrates of the SLC16A11 transporter by in- and efflux experiments using the already generated SLC16A11 overexpressing HEK cells. In addition, using SLC16A11 knockout mice, which we also generated using CRISPR / Cas9 and which are viable also in the homozygous state, we will characterize the metabolic effect of the lack of SLC16A11 for the first time in vivo. With the help of these knockout mice, we will further investigate, whether the hepatic phenotype can be rescued by AAV8-mediated re-expression of SLC16A11 in the liver. Finally, SLC16A11 expression in liver and adipose tissue of patients will be associated with the presence of different components of the metabolic syndrome. Our data will provide first insight how the candidate gene SLC16A11 leads to type 2 diabetes and if the ‘the promise of targeting SLC16A11 [by enhancing its function] as a potential therapy for T2D is to be fulfilled‘.

2型糖尿病是一种在全世界范围内迅速增长的健康威胁。尽管有现代治疗，糖尿病相关的死亡率比未受影响的个体高2-3倍。因此，更深入的了解和更有效的治疗是临床迫切需要的。SLC 16 A11基因编码一元羧酸盐（如丙酮酸盐和乳酸盐）的质膜转运蛋白，在患者全基因组关联研究中显示与2型糖尿病的发展密切相关。具体而言，基因中的单倍型导致SLC 16 A11表达减少和2型糖尿病。原代肝细胞中SLC 16 A11的敲低导致甘油三酯和二酰基甘油（胰岛素抗性的介体）的积累。相反，我们自己的研究表明，在人SLC 16 A11过表达的HEK细胞中，从头脂肪生成显著减少。然而，目前尚不清楚SLC 16 A11如何与脂质代谢改变相关，以及当SLC 16 A11功能受到干扰时，哪些生化，细胞和生理机制导致2型糖尿病。在初步研究中，我们能够证明SLC 16 A11在人和鼠肝脏中强烈表达，并且在小鼠和患者中存在NALFD、胰岛素抵抗和T2 D的情况下，肝脏mRNA表达显著降低。这些数据支持这样的观点，即SLC 16 A11与非酒精性脂肪肝和胰岛素抵抗的发展有关，因此与2型糖尿病有关。因此，我们假设SLC 16 A11通过影响单羧酸盐如乳酸盐和丙酮酸盐的转运而促进非酒精性脂肪肝疾病和胰岛素抵抗的发展，所述单羧酸盐作为脂质代谢的底物，从而降低胰岛素敏感性。通过这个提议，我们的目标是使用已经产生的SLC 16 A11过表达的HEK细胞，通过内排实验和外排实验确定SLC 16 A11转运蛋白的底物。此外，使用SLC 16 A11敲除小鼠，我们也使用CRISPR / Cas9产生并且在纯合状态下也是可行的，我们将首次在体内表征缺乏SLC 16 A11的代谢效应。在这些基因敲除小鼠的帮助下，我们将进一步研究是否可以通过AAV 8介导的SLC 16 A11在肝脏中的重新表达来挽救肝脏表型。最后，患者肝脏和脂肪组织中的SLC 16 A11表达将与代谢综合征的不同组分的存在相关。我们的数据将提供候选基因SLC 16 A11如何导致2型糖尿病的第一个见解，以及“靶向SLC 16 A11 [通过增强其功能]作为T2 D潜在疗法的承诺是否能够实现”。