Sam68 promotes hepatic gluconeogenesis via CRTC2

Aijun Qiao, Junlan Zhou, Shiyue Xu, Wenxia Ma, Chan Boriboun, Teayoun Kim, Baolong Yan, Jianxin Deng, Liu Yang, Eric Zhang, Yuhua Song, Yongchao C. Ma, Stephane Richard, Chunxiang Zhang, Hongyu Qiu, Kirk M. Habegger, Jianyi Zhang and Gangjian Qin ()
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Aijun Qiao: University of Alabama at Birmingham, School of Medicine and School of Engineering
Junlan Zhou: Northwestern University Feinberg School of Medicine
Shiyue Xu: University of Alabama at Birmingham, School of Medicine and School of Engineering
Wenxia Ma: University of Alabama at Birmingham, School of Medicine and School of Engineering
Chan Boriboun: University of Alabama at Birmingham, School of Medicine and School of Engineering
Teayoun Kim: University of Alabama at Birmingham, School of Medicine
Baolong Yan: University of Alabama at Birmingham, School of Medicine and School of Engineering
Jianxin Deng: University of Alabama at Birmingham, School of Medicine and School of Engineering
Liu Yang: University of Alabama at Birmingham, School of Medicine and School of Engineering
Eric Zhang: University of Alabama at Birmingham, School of Medicine and School of Engineering
Yuhua Song: University of Alabama at Birmingham, School of Medicine and School of Engineering
Yongchao C. Ma: Northwestern University Feinberg School of Medicine, Anne & Robert H. Lurie Children’s Hospital of Chicago
Stephane Richard: McGill University
Chunxiang Zhang: University of Alabama at Birmingham, School of Medicine and School of Engineering
Hongyu Qiu: Institute of Biomedical Science Georgia State University
Kirk M. Habegger: University of Alabama at Birmingham, School of Medicine
Jianyi Zhang: University of Alabama at Birmingham, School of Medicine and School of Engineering
Gangjian Qin: University of Alabama at Birmingham, School of Medicine and School of Engineering

Nature Communications, 2021, vol. 12, issue 1, 1-14

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- (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.

Date: 2021
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DOI: 10.1038/s41467-021-23624-9

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