Sam68 promotes hepatic gluconeogenesis via CRTC2
Aijun Qiao, Junlan Zhou, Shiyue Xu, Wenxia Ma, Chan Boriboun, Teayoun Kim, Baolong Yan, Jianxin Deng, Yang Liu, Éric Zhang, Yuhua Song, Yongchao Ma, Stéphane Richard, Chunxiang Zhang, Hongyu Qiu, Kirk M. Habegger, Jianyi Zhang, Gangjian Qin
Abstract
Abstract 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 ΔC ) or N-terminal (Sam68 ΔN ) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68 ΔN 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.