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Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
Published on: October 23, 2018
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Sam68 promotes hepatic gluconeogenesis via CRTC2
Aijun Qiao1, Junlan Zhou2, Shiyue Xu1
1Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL, USA.
Nature Communications
|June 8, 2021
Summary
Sam68 protein regulates hepatic gluconeogenesis, a key process in glucose homeostasis. Sam68 deficiency lowers blood glucose, suggesting it
Area of Science:
- Metabolism
- Molecular Biology
- Endocrinology
Background:
- Hepatic gluconeogenesis is critical for maintaining blood glucose levels.
- Dysregulated gluconeogenesis contributes to type 2 diabetes.
- The precise mechanisms controlling hepatic gluconeogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the role of Sam68, an RNA-binding protein, in regulating hepatic gluconeogenesis.
- To explore Sam68 as a potential therapeutic target for type 2 diabetes.
Main Methods:
- Utilized global and hepatocyte-specific Sam68 knockout mouse models.
- Assessed blood glucose levels and gluconeogenic gene expression.
- Investigated protein levels and interactions of CRTC2, a key gluconeogenic regulator.
- Employed truncated Sam68 mutants to determine domain functions.
Main Results:
- Sam68 deficiency significantly reduced blood glucose and glucagon-induced gluconeogenic gene expression.
- Sam68-deficient hepatocytes showed reduced CRTC2 protein levels, without affecting mRNA.
- Sam68 directly interacts with CRTC2, reducing its ubiquitination and stabilizing its protein.
- Transgenic mice with a specific Sam68 mutation (Sam68ΔN) mimicked the diabetic phenotype of Sam68-deficient mice.
- Hepatic Sam68 expression was elevated in diabetic patients and mouse models.
- Hepatocyte-specific Sam68 deficiency improved hyperglycemia and insulin sensitivity in diabetic mice.
Conclusions:
- Sam68 is a novel regulator of hepatic gluconeogenesis.
- Sam68 stabilizes CRTC2 protein, thereby promoting gluconeogenesis.
- Sam68 represents a potential therapeutic target for managing type 2 diabetes.
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