Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and cellular mechanistic study
PubMed 28743992 · doi:10.1038/s41467-017-00163-w
What was done
Researchers investigated the molecular mechanisms linking elevated lipopolysaccharide (LPS) levels to insulin resistance in high-fat diet-fed and genetically obese (ob/ob) mice. They examined endoplasmic reticulum (ER) stress pathways (specifically IRE1 and XBP1), the subcellular localization and protein expression of the acetyltransferase P300 in hepatocytes, IRS1/2 acetylation status, and the metabolic effects of pharmacological P300 acetyltransferase inhibition in obese mice.
What was found
LPS induced ER stress and elevated P300 expression via the IRE1-XBP1 pathway. In obese mice, P300 translocated from the nucleus to the cytoplasm in hepatocytes. Cytoplasmic P300 acetylated IRS1/2, preventing its association with the insulin receptor and impairing downstream insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity restored insulin sensitivity and lowered hyperglycemia in obese mice. The abstract reports no numerical values or effect sizes.
Why it matters
This study identifies a direct mechanistic link between metabolic endotoxemia, ER stress, and hepatic insulin resistance via P300-mediated IRS1/2 acetylation, highlighting P300 as a candidate drug target for obesity-associated insulin resistance.
Limits
Findings are entirely preclinical, derived from mouse models, and may not translate to human pathophysiology. The abstract does not provide exact sample sizes, numerical endpoints, or safety profiles for pharmacological P300 inhibition.
Cited by
- supports Lipopolysaccharide (LPS) leaking from the gut causes liver issues and impairs insulin signaling and drives inflammation.