Qiao Aijun, Zhou Junlan, Xu Shiyue, Ma Wenxia, Boriboun Chan, Kim Teayoun, Yan Baolong, Deng Jianxin, Yang Liu, Zhang Eric, Song Yuhua, Ma Yongchao C, Richard Stephane, Zhang Chunxiang, Qiu Hongyu, Habegger Kirk M, Zhang Jianyi, Qin Gangjian
Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL, USA.
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nat Commun. 2021 Jun 7;12(1):3340. doi: 10.1038/s41467-021-23624-9.
Hepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68) or N-terminal (Sam68) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68 mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.
肝糖异生对于葡萄糖稳态至关重要，也是2型糖尿病的治疗靶点，但其机制尚未完全明确。在此，我们报告RNA结合衔接蛋白和Src激酶底物Sam68是肝糖异生的新型调节因子。Sam68的全身缺失和肝脏特异性缺失均显著降低血糖水平以及胰高血糖素诱导的糖异生基因表达。在Sam68缺陷型肝细胞中，糖异生关键转录调节因子CRTC2的蛋白水平（而非mRNA水平）比野生型肝细胞低50%以上。Sam68与CRTC2相互作用并减少CRTC2的泛素化。然而，缺乏C端（Sam68）或N端（Sam68）结构域的Sam68截短突变体分别无法结合CRTC2或稳定CRTC2蛋白，并且转基因Sam68小鼠重现了Sam68缺陷型小鼠的血糖和糖异生特征。在糖尿病患者和两种糖尿病小鼠模型中，肝脏Sam68表达也上调，而肝细胞特异性Sam68缺陷可减轻糖尿病小鼠的高血糖并改善胰岛素敏感性。因此，我们的结果确定了Sam68在肝糖异生中的作用，Sam68可能代表糖尿病的治疗靶点。
