Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Full frame distilled prediction
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.
- Candidate categories
- none
- Consensus categories
- none
- Domain
- Candidate signal: noneConsensus signal: none
- Study design
- Candidate signal: Bench or experimentalConsensus signal: Bench or experimental
- Genre
- Candidate signal: EmpiricalConsensus signal: Empirical
- Teacher disagreement score
- 0.063
- Threshold uncertainty score
- 0.350
- Validation status
machine_predicted_unvalidated·codex-gemma-dda1882f352a
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
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.
- Teacher spread
- 0.270 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine beta-synthase. However, the mechanism by which homocysteine promotes the development and progression of hepatic steatosis is unknown. We report here that homocysteine-induced endoplasmic reticulum (ER) stress activates both the unfolded protein response and the sterol regulatory element-binding proteins (SREBPs) in cultured human hepatocytes as well as vascular endothelial and aortic smooth muscle cells. Activation of the SREBPs is associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake and with intracellular accumulation of cholesterol. Homocysteine-induced gene expression was inhibited by overexpression of the ER chaperone, GRP78/BiP, thus demonstrating a direct role of ER stress in the activation of cholesterol/triglyceride biosynthesis. Consistent with these in vitro findings, cholesterol and triglycerides were significantly elevated in the livers, but not plasmas, of mice having diet-induced hyperhomocysteinemia. This effect was not due to impaired hepatic export of lipids because secretion of VLDL-triglyceride was increased in hyperhomocysteinemic mice. These findings suggest a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides. Furthermore, this mechanism likely explains the development and progression of hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
The record
- Venue
- Journal of Clinical Investigation
- Topic
- Endoplasmic Reticulum Stress and Disease
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Hamilton Health SciencesMcMaster University
- Funders
- National Institutes of HealthNational Institute of Neurological Disorders and StrokeAmerican Heart AssociationOffice of Research and DevelopmentNational Institute of Diabetes and Digestive and Kidney DiseasesNational Heart, Lung, and Blood InstituteHeart and Stroke Foundation of CanadaU.S. Department of Veterans Affairs
- Keywords
- Endoplasmic reticulumHyperhomocysteinemiaUnfolded protein responseCystathionine beta synthaseHomocysteineEndocrinologySteatosisInternal medicineLipogenesisCholesterolTriglycerideBiologyFatty liverChemistryBiochemistryLipid metabolismMethionineMedicine
- Has abstract in OpenAlex
- yes