Sam68 promotes hepatic gluconeogenesis via CRTC2

• Published in: Nature communications Vol. 12; no. 1; p. 3340
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/44; 13/89; 13/95; 38/15; 38/39; 631/337/458/582; 631/80/304; 631/80/86/2367; 692/163/2743/137/773; 82/29; 82/80; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animal models; Animals; Binding; Blood; Blood glucose; Blood Glucose - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; DNA-Binding Proteins; Gene expression; Gene Expression Regulation; Genes; Glucagon; Glucagon - metabolism; Gluconeogenesis; Gluconeogenesis - genetics; Gluconeogenesis - physiology; Glucose; Glucose - metabolism; Hepatocytes; Hepatocytes - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Hyperglycemia; Insulin; Insulin Resistance; Kinases; Liver; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Proteins; Ribonucleic acid; RNA; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Substrates; Therapeutic applications; Therapeutic targets; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Transgenic mice; Ubiquitination; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• 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 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. Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.