ArticleThe Journal of biological chemistry2017
TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 103 citations in OpenAlex.
- Mechanotransduction Failure and Molecular Rescue in Gastric Cancer: Kinetotherapy Across the IL-6/STAT3-Myostatin/ACVR2B-Akt/mTOR Axis.Medical sciences (Basel, Switzerland) · 2026Review
- FOXO1 phosphorylation as a context-dependent molecular switch in cancer: from mechanisms to precision therapy.World journal of surgical oncology · 2025Review
- Molecular mechanisms of RACK1-driven metastasis in pancreatic ductal adenocarcinoma revealed by single-cell RNA sequencing.Discover oncology · 2025Article
- CHIP mediates glucagon action on hepatic glucose production via regulating Smad3 ubiquitination.Diabetes, obesity & metabolism · 2025Article
- Effect of resveratrol on key signaling pathways including SIRT1/AMPK/Smad3/TGF-β and miRNA-141 related to NAFLD in an animal model.Research in pharmaceutical sciences · 2025Article
- Article
- Bone morphogenetic protein 8B (BMP8B) increases the glucose sensitivity of ventromedial hypothalamus (VMH) glucose-inhibited (GI) neurons in female mice.microPublication biology · 2025Article
- Integrated plasma metabolomic and proteomic analysis uncover the effects and mechanisms of isotretinoin in severe acne.Frontiers in pharmacology · 2025Article
- A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice.Radiation research · 2024Article
- 1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit.International journal of molecular sciences · 2024Article
- TGF-β1 Signaling Impairs Metformin Action on Glycemic Control.International journal of molecular sciences · 2024Article
- Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function.JCI insight · 2024Article
- Association between single nucleotide polymorphisms, TGF-β1 promoter methylation, and polycystic ovary syndrome.BMC pregnancy and childbirth · 2024Article
- TGFJournal of diabetes research · 2024Article
- Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.Diabetes · 2023Article
- Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-β1-Induced Apoptosis in Hepatocytes.The American journal of pathology · 2023Article
- Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence.Science advances · 2023Article
- Upregulated TGF-β1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling.Diabetologia · 2023Article
- Characterization of Maternal Circulating MicroRNAs in Obese Pregnancies and Gestational Diabetes Mellitus.Antioxidants (Basel, Switzerland) · 2023Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.
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