Abstract 14653: Prevention of Diet-induced Metabolic Dysregulation, Inflammation and Atherosclerosis in Ldlr-/- Mice by Treatment With the ACL Inhibitor ETC-1002
Bibliographic record
Abstract
ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel LDL cholesterol-lowering compound. Preclinical studies revealed that ETC-1002 targets the liver where its metabolite, ETC-1002-CoA, inhibits the synthesis of sterols and fatty acids. The primary mechanism of action is through inhibition of hepatic ATP-citrate lyase (ACL). In the current study we tested the ability of ETC-1002 to prevent diet-induced metabolic dysregulation, inflammation and atherosclerosis in LDL receptor deficient (Ldlr-/-) mice. Ldlr-/- mice fed a high-fat high-cholesterol diet (42% kcal fat; 0.2% cholesterol; HFHC) developed hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity over the 12 week study. ETC-1002 supplementation to the HFHC diet at 3, 10 and 30 mg/kg/d significantly attenuated these metabolic abnormalities in a dose-dependent manner. ETC-1002 + HFHC attenuated plasma triglyceride (up to 64%) and plasma cholesterol concentrations (up to 50%), and improved glucose homeostasis compared to HFHC alone as determined by glucose tolerance tests. Adiposity was attenuated up to 48% with treatment. In liver, ETC-1002 dose dependently prevented cholesterol and triglyceride accumulation up to 75% and 90%, respectively. Hepatic gene expression analysis revealed that treatment significantly reduced the expression of the inflammatory genes Tnfa, Il1b, Ccl3 and Nos2 as well as increased the expression of genes involved in mitochondrial (Cpt1a, 1.3-fold) and peroxisomal (Acox1, 4.1-fold) fatty acid beta-oxidation. ETC-1002 reduced aortic cholesterol ester content by up to 63% and robustly attenuated atherosclerotic lesion development in the aortic sinus by 48%. These studies demonstrate that ETC-1002 effectively prevents plasma and tissue lipid elevations and attenuates the onset of inflammation, leading to the prevention of atherosclerotic lesion development in a mouse model of metabolic dysregulation.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".