Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis
Bibliographic record
Abstract
OBJECTIVE: A novel lipodystrophy syndrome characterized by truncal adiposity, peripheral fat atrophy, type 2 diabetes mellitus, and dyslipidemia occurs in HIV-infected individuals, and may be aggravated by HIV-1 protease inhibitors. The increase in truncal fat could be due to enhanced preadipocyte differentiation. Using the 3T3-L1 preadipocyte model, we reported that ritonavir enhances adipocyte differentiation in culture. The goal of this study was to characterize the molecular mechanism of ritonavir on preadipocyte differentiation. DESIGNS AND METHODS: Time course studies of 3T3-L1 preadipocytes placed in standard differentiation medium (insulin, dexamethasone, and isobutylmethylxanthine) were performed. Glycerol phosphate dehydrogenase (GPDH) was assayed enzymatically, and triacylglycerol (TG) mass was quantified. The adipogenic transcription factors adipocyte determination and differentiation-dependent factor 1 (ADD-1)/sterol regulatory element binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein-alpha (CEBPalpha), and peroxisome proliferator activated receptor-gamma (PPARgamma), were measured by Western analysis. RESULTS: Ritonavir (10 microg/ml) enhanced 3T3-L1 preadipocyte differentiation (30% increase in TG mass; 50% increase in GPDH activity), and transiently raised levels of the 68 kDa active mature form of ADD-1/SREBP-1 during adipogenesis by threefold, compared with standard differentiation. In contrast, ritonavir attenuated the differentiation-induced increase in CEBPalpha and PPARgamma. CONCLUSIONS: Our data suggest that ritonavir enhances 3T3-L1 adipogenesis by increasing the level of active mature ADD-1/SREBP-1. This effect may be due to reduced proteolysis of ADD-1/SREBP-1, as ritonavir inhibits an N-acetyl-leucyl-leucyl-norleucinal (ALLN)-sensitive proteosomal degradation pathway in lymphocytes, and ALLN itself inhibits the breakdown of mature ADD-1/SREBP-1. As mature ADD-1/SREBP-1 regulates several lipogenic enzymes, higher levels may explain the effect of ritonavir on TG accumulation and GPDH activity. Studying ADD-1/SREBP-1 may lead to better understanding and prevention of the lipodystrophy syndrome.
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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".