| First Author | Qiao A | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 3340 |
| PubMed ID | 34099657 | Mgi Jnum | J:324047 |
| Mgi Id | MGI:6725366 | Doi | 10.1038/s41467-021-23624-9 |
| Citation | Qiao A, et al. (2021) Sam68 promotes hepatic gluconeogenesis via CRTC2. Nat Commun 12(1):3340 |
| abstractText | 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(DeltaC)) or N-terminal (Sam68(DeltaN)) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68(DeltaN) 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. |
