Decreased Gluconeogenesis in the Absence of Cystathionine Gamma-Lyase and the Underlying Mechanisms
Bibliographic record
Abstract
AIMS: To investigate the regulation of hepatic glucose production by cystathionine γ-lyase (CSE)-generated hydrogen sulfide (H2S) in hepatic glucose production under physiological conditions. RESULTS: We found that CSE knockout (KO) mice had a reduced rate of gluconeogenesis, which was reversed by administration of NaHS (an H2S donor) (i.p.). Interestingly, isolated CSE KO hepatocytes exhibited a reduced glycemic response to chemical-induced activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and glucocorticoid pathways compared with wild-type (WT) hepatocytes. Treatment with the inhibitors for PKA (KT5720) or glucocorticoid receptor (GR) (RU-486) significantly reduced H2S-stimulated glucose production from both WT and CSE KO mouse hepatocytes. NaHS treatment upregulated the protein levels of key gluconeogenic transcription factors, such as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and CCAAT-enhancer-binding protein-β (C/EBP-β). Moreover, exogenous H2S augmented the S-sulfhydration of the rate-limiting gluconeogenic enzymes and PGC-1α and increased their activities, which were lower in untreated CSE KO hepatocytes. Finally, knockdown of PGC-1α, but not C/EBP-β, significantly decreased NaHS-induced glucose production from the primary hepatocytes. INNOVATION: This study demonstrates the stimulatory effect of endogenous H2S on liver glucose production and reveals three underlying mechanisms; that is, H2S upregulates the expression levels of PGC-1α and phosphoenolpyruvate carboxykinase via the GR pathway; H2S upregulates the expression level of PGC-1α through the activation of the cAMP/PKA pathway as well as PGC-1α activity via S-sulfhydration; and H2S upregulates the expression and the activities (by S-sulfhydration) of glucose-6-phosphatase and fructose-1,6-bisphosphatase. CONCLUSION: This study may offer clues for the homeostatic regulation of glucose metabolism under physiological conditions and its dysregulation in metabolic syndrome.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".