Therapeutic inhibition of RIP1 improves metabolic dysfunction and inhibits atherosclerosis in mouse models of cardiometabolic diseases
Bibliographic record
Abstract
Introduction Chronic activation of the innate immune system drives inflammation and contributes directly to obesity, insulin resistance and atherosclerosis. Previously we showed that necroptosis, a pro‐inflammatory form of programmed cell death, is activated in the vessel wall and drives atherosclerosis via activation of RIP3 and MLKL. We sought to determine upstream genetic regulators of necroptosis in atherosclerosis and metabolic disease, and hypothesized that gene expression of RIP1, a key regulatory kinase upstream of NFkB activation, apoptosis and necroptosis, drives macrophage inflammation in cardiometabolic diseases. Methods RIP1 anti‐sense oligonucleotides (ASOs, 2 unique sequences) were used to reduce RIP1 expression in 2 mouse models: i) atherosclerotic model [ApoE −/− mice fed a western diet for 8wks] and ii) diet‐induced obesity (DIO) model [C57Bl/6 male mice fed a high fat diet for 24 wks]. Mice were given weekly injections of RIP1 ASOs (50 or 100mg/kg) or control ASO (non‐targeting). Results RIP1 ASO treated ApoE −/− mice had a marked reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, p<0.01) and plasma inflammatory cytokines (IL‐1a, IL‐17A, p<0.05). RIP1 knockdown in macrophages decreased inflammatory gene expression (NFkB, TNFa, IL‐1a) and in vivo LPS‐induced NFkB activation. In obese mice, RIP1 ASOs strikingly decreased body weight (25% decrease versus control p<0.001) and total fat mass (50–65% decrease versus control, p<0.001). Further, insulin resistance was improved in RIP1 ASO treated mice (fasted blood glucose: 10.9mM in control versus 8.5±mM in RIP1 ASO, p<0.001; GTT and ITT both p<0.001). In humans, we identified 5 novel SNPs in strong linkage disequilibrium in or nearby RIP1 gene exon 5. Notably, in a cohort of >1,800 people, individuals carrying the minor allele of these RIP1 SNPs have a 75–89% increase in the risk of developing obesity (adjusted odds ratios: 1.75–1.89, p<10 −5 ) and a significant increase in RIP1 mRNA expression in adipose tissue (eQTL association in METSIM cohort, p=10 −23 ). Conclusions : We have identified RIP1 as central a driver of insulin resistance, obesity, and atherosclerosis and demonstrate the potential of RIP1 as a novel therapeutic target. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. 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.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 |
| 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)
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 teacher head, 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".