ArticleAmerican journal of physiology. Endocrinology and metabolism2014
Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids.
Article in American journal of physiology. Endocrinology and metabolism, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 40 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
40 citing papers in PubMed, 66 citations in OpenAlex.
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- Effect of a high dose atorvastatin as added-on therapy on symptoms and serum AMPK/NLRP3 inflammasome and IL-6/STAT3 axes in patients with major depressive disorder: randomized controlled clinical study.Frontiers in pharmacology · 2024Article
- Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarkers Involved in Pulmonary Tuberculosis and Pulmonary Tuberculosis-Complicated Diabetes.Microbiology spectrum · 2023Article
- The Antitumor Effect of Cinnamaldehyde Derivative CB-PIC in Hepatocellular Carcinoma Cells via Inhibition of Pyruvate and STAT3 Signaling.International journal of molecular sciences · 2022Article
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- Notch Signaling and Cross-Talk in Hypoxia: A Candidate Pathway for High-Altitude Adaptation.Life (Basel, Switzerland) · 2022Review
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- Dihydroxyacetone suppresses mTOR nutrient signaling and induces mitochondrial stress in liver cells.PloS one · 2022Article
- Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2021Review
- Deletion ofAutophagy · 2021Article
- Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: targeting mTORC1.Journal of molecular medicine (Berlin, Germany) · 2021Review
- Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism.Scientific reports · 2021Article
- Pannexin 3 regulates skin development via Epiprofin.Scientific reports · 2021Article
- AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation.Genes & development · 2020Article
- Triclosan induces ROS-dependent cell death and autophagy in A375 melanoma cells.Oncology letters · 2020Article
- Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice.Diabetes & metabolism journal · 2020Article
- Nrf2-SHP Cascade-Mediated STAT3 Inactivation Contributes to AMPK-Driven Protection Against Endotoxic Inflammation.Frontiers in immunology · 2020Article
- A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress.International journal of molecular sciences · 2019Article
- Association of sustained supraphysiologic hyperinsulinemia and inflammatory signaling within the digital lamellae in light-breed horses.Journal of veterinary internal medicine · 2019Article
Corrections and comments
- Correction · 2016-11-15Error in Image · Updated to Retraction ·
- Retraction · 2022-10-11Duplication of/in Image · Investigation by Company/Institution · Upgrade/Update of Prior Notice(s) ·
- Erratum issuedCorrigendum.2016
- Retracted
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Nutrient overload is associated with the development of obesity, insulin resistance, and type 2 diabetes. However, the underlying mechanisms for developing insulin resistance in the presence of excess nutrients are incompletely understood. We investigated whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic insulin resistance that is induced by the consumption of a high-protein diet (HPD) and the presence of excess amino acids. Exposure of HepG2 cells to excess amino acids reduced AMPK phosphorylation, upregulated Notch1 expression, and impaired the insulin-stimulated phosphorylation of Akt Ser(473) and insulin receptor substrate-1 (IRS-1) Tyr(612). Inhibition of Notch1 prevented amino acid-induced insulin resistance, which was accompanied by reduced expression of Rbp-Jk, hairy and enhancer of split-1, and forkhead box O1. Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). Activation of AMPK by metformin inhibited mTORC1-STAT3 signaling, thereby preventing excess amino acid-impaired insulin signaling. Finally, HPD feeding suppressed AMPK activity, activated mTORC1/STAT3/Notch1 signaling, and induced insulin resistance. Chronic administration of either metformin or rapamycin inhibited the HPD-activated mTORC1/STAT3/Notch1 signaling pathway and prevented hepatic insulin resistance. We conclude that the upregulation of Notch1 expression by hyperactive mTORC1 signaling is an essential event in the development of hepatic insulin resistance in the presence of excess amino acids. Activation of AMPK prevents amino acid-induced insulin resistance through the suppression of the mTORC1/STAT3/Notch1 signaling pathway.
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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.