Alterations of Gut Microbiota by Overnutrition Impact Gluconeogenic Gene Expression and Insulin Signaling

Abstract

A high-fat, Western-style diet is an important predisposing factor for the onset of type 2 diabetes and obesity. It causes changes in gut microbial profile, reduction of microbial diversity, and the impairment of the intestinal barrier, leading to increased serum lipopolysaccharide (endotoxin) levels. Elevated lipopolysaccharide (LPS) induces acetyltransferase P300 both in the nucleus and cytoplasm of liver hepatocytes through the activation of the IRE1-XBP1 pathway in the endoplasmic reticulum stress. In the nucleus, induced P300 acetylates CRTC2 to increase CRTC2 abundance and drives Foxo1 gene expression, resulting in increased expression of the rate-limiting gluconeogenic gene G6pc and Pck1 and abnormal liver glucose production. Furthermore, abnormal cytoplasm-appearing P300 acetylates IRS1 and IRS2 to disrupt insulin signaling, leading to the prevention of nuclear exclusion and degradation of FOXO1 proteins to further exacerbate the expression of G6pc and Pck1 genes and liver glucose production. Inhibition of P300 acetyltransferase activity by chemical inhibitors improved insulin signaling and alleviated hyperglycemia in obese mice. Thus, P300 acetyltransferase activity appears to be a therapeutic target for the treatment of type 2 diabetes and obesity.

Obesity Modulates the Gut Microbiome in Triple-Negative Breast Cancer

“…It is possible that this relative increase in our model may be secondary to increased mucus production, which is stimulated by LPS and inflammatory cytokines [68]. Overnutrition is known to increase plasma LPS through altered intestinal barrier permeability [69]. A prolonged period of overnutrition with a Western diet may have produced sustained endotoxemia and a secondary increase in intestinal mucus.…”

The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor

“…Increased bacterial lipopolysaccharide (LPS) leakage from the gut into circulation and its initiated low-grade of inflammation play important roles in the development of insulin resistance in obesity and T2D (3,(32)(33)(34). We found that LPS can induce P300 in hepatocytes via reduction of the ubiquitination and degradation of P300, and elevated P300 impairs insulin signaling by acetylating IRS1 and 2 (27,35). Of note, P300 is a big protein, however, this protein has a relatively short half-life (5 h) (36), indicating that continuous protein translation in the cytoplasm is required to maintain the cellular P300 protein levels.…”

Co-toxicity of Endotoxin and Indoxyl Sulfate, Gut-Derived Bacterial Metabolites, to Vascular Endothelial Cells in Coronary Arterial Disease Accompanied by Gut Dysbiosis

“…Thus, Bacteroidetes may have the potential to regulate atherosclerosis progression [ 30 ]. Moreover, lipid A of LPS from Bacteroides is an antagonist of immune stimulation and inflammatory cytokine response [ 31 , 40 ]. Furthermore, the study demonstrated an increase in the prominent bacterial families producing indole, i.e., Enterobacteriaceae , Clostridiaceae , and Verrucomicrobiace in CAD patients, which although statistically insignificant, was correlated with an increased indoxyl level which was twice as high as in healthy subjects.…”