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SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells.

ABSTRACT: The regulation of hepatic gluconeogenesis is of great significance to improve insulin resistance and benefit diabetes therapy. cAMP-Regulated Transcriptional Co-activator 2 (CRTC2) plays a key role in regulating hepatic gluconeogenesis through controlling the expression of gluconeogenic rate-limiting enzymes such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Recently, salt-inducible kinase 1 (SIK1) has been identified to play an important role in glucose metabolism disorders, but whether and how SIK1 regulates the CTRC2 signaling in liver cells under high glucose conditions has rarely been intensively elucidated. Here, we show that high glucose stimulation resulted in time-dependent down-regulated expression of SIK1, phosphorylated SIK1 at T182 site, and phosphorylated CRTC2 at S171 site, as well as upregulated expression of total CRTC2 and its downstream targets G6Pase and PEPCK in the human liver cell line HepG2. The nuclear expression levels of SIK1 and CRTC2 were time-dependently upregulated upon high glucose challenge, which was accompanied by enhanced cytoplasm-to-nucleus translocation of SIK1. Manipulation of SIK1 activity using plasmid-mediated SIK1 over-expression and the use of the SIKs inhibitor HG-9-91-01 confirmed that SIK1 regulated the CRTC2 signaling pathway in HepG2 cells. Furthermore, in mouse primary hepatocytes, high glucose exposure down-regulated SIK1 expression, and promoted SIK1 nuclear accumulation. While HG-9-91-01 treatment suppressed SIK1 expression and released the inhibitory effects of SIK1 on the expressions of key molecules involved in the CRTC2 signaling pathway, additional ectopic expression of SIK1 using adenovirus infection reversed the impacts of HG-9-91-01 on the expressions of these molecules in mouse hepatocytes. Therefore, SIK1 regulates CRTC2-mediated gluconeogenesis signaling pathway under both physiological and high glucose-induced pathological conditions. The modulation of the SIK1-CRTC2 signaling axis could provide an attractive means for treating diabetes.

SUBMITTER: Wang C

PROVIDER: S-EPMC7493656 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells.

Wang Chang C Song Daofei D Fu Jiahui J Wen Xiuying X

Frontiers in endocrinology 20200902

The regulation of hepatic gluconeogenesis is of great significance to improve insulin resistance and benefit diabetes therapy. cAMP-Regulated Transcriptional Co-activator 2 (CRTC2) plays a key role in regulating hepatic gluconeogenesis through controlling the expression of gluconeogenic rate-limiting enzymes such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Recently, salt-inducible kinase 1 (SIK1) has been identified to play an important role in glucose metabo ...[more]

PMID: 33013689

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Project description:BackgroundAs a compound Chinese medicine, Zhenqing Recipe (ZQR) has been shown to ameliorate hyperglycemia, hyperlipidemia, fatty liver and insulin resistance in patients with diabetes and diabetic rats. In this paper, we further examined the effect of ZQR on diabetes complicated by non-alcoholic fatty liver disease (NAFLD) and the underlying molecular mechanisms.MethodsDiabetic rats with NAFLD were developed by a high-fat diet (HFD) with low-dose streptozotocin (STZ) injection for 4 weeks. These rats were randomly separated into the diabetic model (DM), ZQR, metformin (Met), adenovirus expressing-salt-induced kinase 1 (Ad-SIK1) and adenovirus labeled with green fluorescent protein (Ad-GFP) groups. The effects on hepatic expression of gluconeogenic genes, glycolipid metabolism and pathological changes were subsequently detected.ResultsSerum glucose, triglycerides (TG), total cholesterol (TC) and hepatic TG were reduced in the ZQR group. The histopathological and immunohistochemical changes in the liver and pancreas in the ZQR group were significantly alleviated. The decrease of SIK1 expression was observed in the liver of diabetic rats induced by HFD and STZ. SIK1 overexpression in the liver relieved hyperglycemia, hyperlipidemia and fatty liver. Both the mRNA and protein levels of CREB-regulated transcription co-activator 2 (CRTC2), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in the liver were drastically reduced, whereas those of SIK1 were markedly increased in the ZQR group compared to levels in the DM group. Compared with the DM group, Ser577 phosphorylation of SIK1 was obviously reduced in the liver, while T182 phosphorylation of SIK1 and S171 phosphorylation of CRTC2 were evidently increased in the Ad-SIK1, Met and ZQR groups.ConclusionsZQR ameliorates hepatic gluconeogenesis and lipid storage in diabetic rats induced by HFD and STZ by activating the SIK1/CRTC2 signaling pathway. Upregulating hepatic SIK1 by ZQR may represent an efficient strategy for treating diabetes with NAFLD.

Project description:ObjectiveSalt-induced kinase 1 (SIK1) acts as a key modulator in many physiological processes. However, the effects of SIK1 on gluconeogenesis and the underlying mechanisms have not been fully elucidated. In this study, we found that a natural compound phanginin A could activate SIK1 and further inhibit gluconeogenesis. The mechanisms by which phanginin A activates SIK1 and inhibits gluconeogenesis were explored in primary mouse hepatocytes, and the effects of phanginin A on glucose homeostasis were investigated in ob/ob mice.MethodsThe effects of phanginin A on gluconeogenesis and SIK1 phosphorylation were examined in primary mouse hepatocytes. Pan-SIK inhibitor and siRNA-mediated knockdown were used to elucidate the involvement of SIK1 activation in phanginin A-reduced gluconeogenesis. LKB1 knockdown was used to explore how phanginin A activated SIK1. SIK1 overexpression was used to evaluate its effect on gluconeogenesis, PDE4 activity, and the cAMP pathway. The acute and chronic effects of phanginin A on metabolic abnormalities were observed in ob/ob mice.ResultsPhanginin A significantly increased SIK1 phosphorylation through LKB1 and further suppressed gluconeogenesis by increasing PDE4 activity and inhibiting the cAMP/PKA/CREB pathway in primary mouse hepatocytes, and this effect was blocked by pan-SIK inhibitor HG-9-91-01 or siRNA-mediated knockdown of SIK1. Overexpression of SIK1 in hepatocytes increased PDE4 activity, reduced cAMP accumulation, and thereby inhibited gluconeogenesis. Acute treatment with phanginin A reduced gluconeogenesis in vivo, accompanied by increased SIK1 phosphorylation and PDE4 activity in the liver. Long-term treatment of phanginin A profoundly reduced blood glucose levels and improved glucose tolerance and dyslipidemia in ob/ob mice.ConclusionWe discovered an unrecognized effect of phanginin A in suppressing hepatic gluconeogenesis and revealed a novel mechanism that activation of SIK1 by phanginin A could inhibit gluconeogenesis by increasing PDE4 activity and suppressing the cAMP/PKA/CREB pathway in the liver. We also highlighted the potential value of phanginin A as a lead compound for treating type 2 diabetes.

Dataset Information

SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells.

Publications

SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells.

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