Abstract 11802: IRF2BP2 Regulates Hormone Sensitive Lipase and Lipolysis in Human Adipocytes and in Mice
Bibliographic record
Abstract
Background: IRF2BP2, a transcriptional co-factor, has emerged as a potential regulator of circulating lipid levels based on several coronary artery disease (CAD) genome-wide association studies (GWAS) studies. However, the role of IRF2BP2 in adipocytes, which regulate fat storage, energy expenditure, and fatty acid release, remains unexplored. Our aim is to investigate the role of IRF2BP2 in adipocyte function regulation. Methods: Human adipocyte stem cells (hASC) were differentiated into adipocytes for in vitro studies. We used the CRISPR system and lentiviral expression constructs to knockout (KO) and overexpress (OE) IRF2BP2. Control, IRF2BP2 KO and IRF2BP2 OE adipocytes were assessed by several methods, including RNA-seq, western blot analysis, and functional assessment of lipolysis and glucose uptake. IRF2BP2 chromatin immunoprecipitation (ChIP)-seq was performed in vitro . Adiponectin-Cre mice were crossed with Irf2bp2 flox/flox mice to generate adipocyte-specific KO (AKO) animals. We evaluated the effect of IRF2BP2 KO on adipose morphology and gene profiles. Circulating fatty acids were assessed in control and AKO mice. Results: IRF2BP2 deletion or OE in hASC-differentiated adipocytes did not affect adipocyte differentiation or glucose uptake. However, triglyceride lipolysis was markedly increased in KO cells. Conversely, IRF2BP2 OE suppressed lipolysis. RNA-seq analysis of control vs. IRF2BP2 KO or OE cells identified the enrichment of lipid catabolic pathways. Notably, IRF2BP2 KO upregulated, whereas IRF2BP2 OE downregulated the mRNA and protein levels of LIPE (i.e. hormone sensitive lipase, or HSL). Further, ChIP-seq analysis demonstrates strong binding of IRF2BP2 to a LIPE enhancer, suggesting direct regulation. In mice, Irf2bp2 AKO increased circulating fatty acids, accompanied by a reduction of adipocyte size. LIPE mRNA and protein expression in adipose tissue was also elevated. Finally, Irf2bp2 AKO induces massive adipose tissue inflammation, evidenced by F4/80 staining and chemotaxis gene markers expression. Conclusions: We established IRF2BP2, as a novel transcriptional regulator of adipocyte lipolysis, through the key lipolytic gene LIPE, which may shed light on deciphering the role of IRF2BP2 in CAD.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.017 | 0.006 |
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".