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

• Published in: International journal of molecular sciences 2021-02, Vol.22 (4), p.2121
• Main Author: He, Ling
• Format: Article
• Language: English
• Subjects: Acetyltransferase; acetyltransferase P300; Animals; Bacteria; Chemical activity; Cytoplasm; Diabetes; Diabetes mellitus (non-insulin dependent); Diet; Digestive system; Endoplasmic reticulum; Endotoxins; FOXO1 protein; Gastrointestinal Microbiome - genetics; Gene expression; Gene Expression Regulation; Gluconeogenesis - genetics; gluconeogenic gene; Glucose; Hepatocytes; High fat diet; Humans; Hyperglycemia; Hypoglycemia; Inflammation; Insulin; Insulin - metabolism; insulin resistance; Intestinal microflora; Intestine; Kinases; Lipids; lipopolysaccharide; Lipopolysaccharides; Liver; Metabolism; Microbiota; Microorganisms; Nuclei (cytology); Obesity; Overnutrition; Overnutrition - blood; Overnutrition - genetics; Overnutrition - microbiology; Pandemics; Permeability; Phosphorylation; Proteins; Review; RNA polymerase; Signal Transduction; Transcription factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22042121

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 gene expression, resulting in increased expression of the rate-limiting gluconeogenic gene and 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 and 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.