ArticleThe Journal of biological chemistry2010
AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 164 citations in OpenAlex.
- Adenovirus 36 attenuates weight loss from exercise but improves glycemic control by increasing mitochondrial activity in the liver.PloS one · 2014Trial
- Metformin's disruption of gluconeogenesis in type 2 diabetes impairments of the cori and alanine cycles as hidden drivers of metabolic waste accumulation, NF-κBHIF-1α-mediated low-grade inflammation, and multisystem dysfunction.Problemy endokrinologii · 2026Review
- The AMPK/NRF2/FOXO Axis in CKD-Molecular and Clinical Perspectives.Antioxidants (Basel, Switzerland) · 2026Review
- Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.Medical gas research · 2025Review
- AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy.CNS neuroscience & therapeutics · 2025Review
- Review
- Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology.Current medicinal chemistry · 2025Review
- Bioactive fraction isolated fromFrontiers in pharmacology · 2025Article
- Strategy for treating MAFLD: Electroacupuncture alleviates hepatic steatosis and fibrosis by enhancing AMPK mediated glycolipid metabolism and autophagy in T2DM rats.Diabetology & metabolic syndrome · 2024Article
- New advances of adiponectin in regulating obesity and related metabolic syndromes.Journal of pharmaceutical analysis · 2024Review
- Metformin: From Diabetes to Cancer-Unveiling Molecular Mechanisms and Therapeutic Strategies.Biology · 2024Review
- Targeting the Metabolic Paradigms in Cancer and Diabetes.Biomedicines · 2024Review
- Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.Signal transduction and targeted therapy · 2023Review
- Biological functions of CRTC2 and its role in metabolism-related diseases.Journal of cell communication and signaling · 2023Review
- Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway.Experimental & molecular medicine · 2023Article
- The development and benefits of metformin in various diseases.Frontiers of medicine · 2023Review
- Emerging Role of SMILE in Liver Metabolism.International journal of molecular sciences · 2023Review
- The Synergistic Action of Metformin andInternational journal of molecular sciences · 2023Article
- Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae.Heliyon · 2022Review
- Targeting hepatic sulfane sulfur/hydrogen sulfide signaling pathway with α-lipoic acid to prevent diabetes-induced liver injury via upregulating hepatic CSE/3-MST expression.Diabetology & metabolic syndrome · 2022Article
25 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
Abstract
Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of gluconeogenic enzyme gene expression. Here, we show that SHP inhibited protein kinase A-mediated transcriptional activity of cAMP-response element-binding protein (CREB), a major regulator of glucose metabolism, to modulate hepatic gluconeogenic gene expression. Deletion analysis of phosphoenolpyruvate carboxykinase (PEPCK) promoter demonstrated that SHP inhibited forskolin-mediated induction of PEPCK gene transcription via inhibition of CREB transcriptional activity. In vivo imaging demonstrated that SHP inhibited CREB-regulated transcription coactivator 2 (CRTC2)-mediated cAMP-response element-driven promoter activity. Furthermore, overexpression of SHP using adenovirus SHP decreased CRTC2-dependent elevations in blood glucose levels and PEPCK or glucose-6-phosphatase (G6Pase) expression in mice. SHP and CREB physically interacted and were co-localized in vivo. Importantly, SHP inhibited both wild type CRTC2 and S171A (constitutively active form of CRTC2) coactivator activity and disrupted CRTC2 recruitment on the PEPCK gene promoter. In addition, metformin or overexpression of a constitutively active form of AMPK (Ad-CA-AMPK) inhibited S171A-mediated PEPCK and G6Pase gene expression, and hepatic glucose production and knockdown of SHP partially relieved the metformin- and Ad-CA-AMPK-mediated repression of hepatic gluconeogenic enzyme gene expression in primary rat hepatocytes. In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.