Elimination of hepatocyte‐derived <scp>DPP4</scp> downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice
Bibliographic record
Abstract
The association between metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease is well characterized; however, the underlying mechanism is incompletely understood. Interestingly, hepatocyte-specific silencing of dipeptidyl peptidase 4 (DPP4) prevents liver fibrosis and adipose tissue inflammation; however, how this affects the heart remains to be investigated. This study evaluates how diastolic function and molecular signatures of heart failure, like inflammation and fibrosis, are affected in male Dpp4+/+, Dpp4-/-, and Dpp4flox/flox mice injected with a TBG-CRE to selectively eliminate DPP4 from hepatocytes (Dpp4hep-/-) and respective controls (Dpp4GFP), aged and fed an HFHC diet for 24 weeks. Mice underwent pulsed-wave and tissue Doppler echocardiography. Further, speckle-tracking strain analysis was performed to detect diastolic dysfunction. Differential mRNA analysis using the NanoString platform and qRT-PCR were conducted using ventricular tissue to assess immunological pathway expression, as well as hypertrophy, modeling-related, senescence, and metabolism gene expression. Immunological pathway analysis of ventricular tissue revealed downregulation of 12 immune-related pathways in Dpp4hep-/- mice, including apoptosis and chemokine and cytokine signaling; however, this was not observed in Dpp4-/- mice. Further, fibrosis and ECM modeling-related genes, Col1a1, Col3a1, Ctgf, and Myh7, were significantly upregulated in Dpp4-/- mice but unchanged in Dpp4hep-/- mice, compared to controls. Interestingly, cardiac hypertrophy and systolic and diastolic function evaluated with echocardiography were unchanged. Immune-related pathways are downregulated in Dpp4hep-/- mice, while fibrosis genes are significantly upregulated in Dpp4-/- mice, compared to respective controls. Despite these molecular changes, cardiac hypertrophy and systolic and diastolic function were unchanged with systemic and organ-specific loss of Dpp4.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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".