TY - JOUR
T1 - Sam68 promotes hepatic gluconeogenesis via CRTC2
AU - Qiao, Aijun
AU - Zhou, Junlan
AU - Xu, Shiyue
AU - Ma, Wenxia
AU - Boriboun, Chan
AU - Kim, Teayoun
AU - Yan, Baolong
AU - Deng, Jianxin
AU - Yang, Liu
AU - Zhang, Eric
AU - Song, Yuhua
AU - Ma, Yongchao C.
AU - Richard, Stephane
AU - Zhang, Chunxiang
AU - Qiu, Hongyu
AU - Habegger, Kirk M.
AU - Zhang, Jianyi
AU - Qin, Gangjian
N1 - Funding Information:
We thank Dr. Marc Montminy (Salk Institute for Biological Studies) for generously providing pcDNA3-Flag-CRTC2K628R plasmid and CRTC2K628R expressing adenoviral vector. We thank Mr. Rory A Greer for assistance in text pattern search and hydropathy analysis for protein binding site prediction. We thank the UAB Small Animal Phenotyping and Glycemic Clamp Cores supported by the National Institutes of Health Nutrition Obesity Research Centers (P30-DK-056336). This work was supported by the National Institute of Health (R01 Grants# HL113541, HL130052, HL131110, and HL138990 to G. Q.; HL142291 to H. Q and G. Q.; 1R01DK112934 to K. M. H); American Diabetes Association (Grant# 1-15-BS-148 to G.Q.); American Heart Association (Grant# 19TPA34910227 to G. Q.; 19CDA34630052 to A. Q.; 18POST34070088 to S. X; and 18PRE34080358 to E. Z.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN 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.
AB - 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- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN 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.
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U2 - 10.1038/s41467-021-23624-9
DO - 10.1038/s41467-021-23624-9
M3 - Article
C2 - 34099657
AN - SCOPUS:85107552211
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3340
ER -