Human Resistin Stimulates Hepatic Overproduction of Atherogenic ApoB-Containing Lipoprotein Particles by Enhancing ApoB Stability and Impairing Intracellular Insulin Signaling
Bibliographic record
Abstract
RATIONALE: Obese individuals are at high risk for developing atherosclerosis primarily attributable to elevated plasma concentrations of apolipoprotein (apo)B-containing particles, including very-low-density lipoprotein (VLDL). Plasma levels of the adipose tissue adipokine resistin are increased in human obesity, and resistin expression is positively correlated with coronary atherosclerosis and VLDL levels. OBJECTIVE: We sought to determine for the first time whether resistin directly stimulates human hepatocyte production of apoB-containing particles and to elucidate the mechanisms responsible. METHODS AND RESULTS: Treatment of human hepatocytes with resistin at levels observed in human obesity stimulated apoB secretion up to 10-fold, because of increased microsomal triglyceride transfer protein (MTP) activity and decreased expression/phosphorylation of proteins in the insulin signaling pathways (insulin receptor substrate-2, Akt, and extracellular signal-regulated kinase). Resistin also increased hepatocyte lipid content by stimulating de novo lipogenesis via the SREBP1 and SREBP2 pathways. Furthermore, obese serum with elevated resistin levels induced greater hepatocyte stimulation of apoB secretion than lean human serum, an effect that was ameliorated by antibody immunoprecipitation removal of serum resistin. CONCLUSIONS: Resistin has a direct deleterious impact on human hepatic lipid and lipoprotein regulation. Resistin greatly increased hepatocyte VLDL apoB and lipid secretion because of MTP activation and induction of hepatocyte insulin resistance. Conversely, antibody removal of serum resistin ameliorated human serum stimulation of apoB secretion. Increased hepatic cellular lipids mediated by resistin reflects the fatty liver/steatosis observed with elevated resistin in humans. Thus, human resistin is a novel therapeutic target for mitigating common hepatic pathophysiological processes associated with human obesity, dyslipidemia and atherosclerosis.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".