Bibliographic record
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging independent risk factor for cardiovascular disease (CVD). However, our current understanding of the underlying mechanism by which fatty liver per se increases atherosclerosis risk remains unclear and is difficult to delineate due to its common association with other metabolic abnormalities. In this thesis, genetically modified atherosclerosis-prone ApoE-null and Ldlr-null mouse models were used to investigate the essential role of hepatic Jak2 in atherogenesis. I assessed the role of circulating IGF-1 as a mechanistic link between NAFLD and atherosclerosis. In chapter 4, I describe the consequences of deleting hepatic Jak2 on atherosclerosis development and progression. I show that hepatic Jak2-deficiency resulted in profound fatty liver without other confounding cardiovascular risk factors, and this was accompanied by accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. Furthermore, I demonstrate that reduced circulating IGF-1 played a causal role in exacerbating atherosclerosis that occurred with hepatic Jak2-deficiency, which was attenuated by pharmacologic or genetic restoration of circulating IGF-1. I next assessed the essential role of hepatic IGF-1 in atherogenesis. In chapter 5, I show that disruption of hepatic Igf1 and reduction of circulating IGF-1 did not phenocopy hepatic Jak2-deficient mice with accelerated atherosclerosis. In fact, hepatic Igf1-deficiency led to a significant reduction in atherosclerosis particularly in female mice. Interestingly, female hepatic Igf1-deficient mice also displayed profound hepatic steatosis with reduced circulating IL-6 and triglycerides. Taken together, the results presented in this thesis reveal a novel mechanistic link between NAFLD and atherosclerosis through hepatic Jak2 that provides atheroprotection. While restoration of IGF-1 partially attenuates the accelerated atherosclerosis in hepatic Jak2-deficient mice, endogenous hepatic IGF-1 does not appear to be essential in atheroprotection. These results illustrate the complexity in the regulation of atherosclerosis that is mediated by hepatic JAK2 signaling. Clear understanding of how hepatic signaling affects atherosclerosis can lead to novel therapeutic strategies to combat CVD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".