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.
Highlights
Departments of Pediatrics and Pharmacology & Molecular Sciences, Johns Hopkins University School of Citation: He, L
In response to the decrease in blood glucose levels, counterregand glucocorticoids to increase liver glucose production directly or indirectly through ulatory mechanisms are activated by rapidly inducing the secretion of glucagon, epinephthe cAMP-PKA signaling pathway [38]
We found that depletion of liver P300 decreased glycogen storage in the liver, leading to relative hypoglycemia [54]
Summary
After birth, the baby acquires bacteria from the mother and surrounding environment. There are four major microbial phyla: Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria, that account for over 90% of the gut microbiota, of which Bacteroides are considered good bacteria [6,7]. 2. Overnutrition Leads to Changes in the Composition of Gut Microbiota conditions of the Creative Commons. High-fat-diet (HFD) feeding can change the gut microbial profile and reduce its diversity. Over 200 strains of mice were used to determine the effects of dietary factors on gut microbiota and reported that feeding a high-fat and high-sugar diet reproducibly altered gut microbiota despite differences in the host genotype [20]. Of importance, most diet-induced changes in gut microbiota are reversible [20]
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