Abstract 14589: Adiponectin Inhibits Hepatic Production of Triglyceride-Rich Apolipoprotein B Lipoproteins Through Both LDL-Receptor Dependent and Independent Mechanisms
Bibliographic record
Abstract
Background and Rationale: Increasing plasma concentrations of the anti-inflammatory protein, adiponectin, are significantly and independently associated with a lower risk of coronary heart disease (CHD), while hypoadiponectinemia, conversely, is a strong risk factor for CHD. The mechanisms by which adiponectin mediates its cardioprotective role are not clearly understood. Here, we have elucidated a key cause of the cardioprotective effect of adiponectin, involving a direct inhibitory action on hepatic production of pro-atherogenic triglyceride-rich apolipoprotein B (apoB) lipoproteins, mediated through both LDL-receptor dependent mechanisms, involving PCSK9, and LDL-receptor independent mechanisms. Methods and Results: Cultured human hepatocytes (HepG2 cells) and primary human hepatocytes were treated with physiological concentrations of purified recombinant human adiponectin (10 μg/mL) for 24 hours. Adiponectin treatment reduced endogenous apoB cellular expression and secretion markedly by 60% and 30%, respectively, (P<0.01). Adiponectin also reduced apoB production stimulated by prior treatment of cells with oleate or with pro-inflammatory obese human serum (25% reduction for both, P<0.01). Adiponectin-mediated inhibition of cellular apoB production occurred through a substantial increase in levels of hepatocyte LDL-receptors (70%, P<0.01), which promote proteasome-mediated apoB degradation, and which resulted from a 50% reduction in cellular PCSK9 levels (P<0.01 for both). Multiple LDL-receptor independent effects of adiponectin involved mechanisms which reduce cellular apoB stability: (1) a decrease in cellular microsomal triglyceride transfer protein (MTP) (by 25%, (P<0.01); (2) an increase in AMP kinase (by 40%, P<0.01); and (3) marked stimulation of the Akt/Erk insulin signaling pathways. Conclusions: Adiponectin has a direct mitigating effect on hepatic apoB production through mechanisms mediated in part by the LDL-receptor and PCSK9, MTP and the insulin signaling pathway. These findings indicate that that inhibition of apoB may explain in large part adiponectin’s cardioprotective role. Furthermore, targeted adiponectin-based therapies may be a novel approach to inhibit hepatic apoB production.
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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) | 0.001 | 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) | 0.007 | 0.002 |
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".