Abstract
Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.
Highlights
Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation
We found that depletion of XBP1 by adenoviral shRNA abolished LPS-mediated P300 induction in Hepa[1,2,3,4,5,6] cells (Fig. 3d), and P300 could not be induced by an high-fat diet (HFD) in liverspecific XBP1 knockout mice[28] (Fig. 3e and Supplementary Fig. 2e)
Increased LPS leakage from the gut has emerged as one of the most appealing mechanisms to explain the connections between changes in the intestinal microbiome and insulin resistance[15, 18, 19, 42], but the mechanism underlying the impairment of hepatic insulin signaling is not well understood
Summary
The induction of acetyltransferase P300 in the liver of obese mice. A high-fat, western-style diet is an important predisposing factor for the onset of diabetes and obesity. Considering that acetyltransferase P300 and CBP are critical co-activators in the regulation of hepatic glucose production[23, 24], we determined the protein levels of these co-activators in the liver of mice fed an HFD. Hepatic P300 protein levels increased dramatically 1 week after feeding the HFD and before the onset of insulin resistance; the mRNA levels of P300 did not change significantly (Fig. 1d and Supplementary Fig. 1b), suggesting that the induction of P300 occurred at the post-transcriptional level. A, d Each lane represents a mouse sample conjugated P300 and increased P300 protein levels (Fig. 2e), indicating that LPS mediates P300 induction by decreasing its ubiquitination and degradation. P300 is a nuclear protein in untreated cells, but LPS treatment led to the cytoplasmic localization of P300 in hepatocytes (Fig. 2h, i and Supplementary Fig. 1g). We found that ER stress triggered by thapsigargin or tunicamycin, an agent widely used to model cellular ER stress, led to the P300 induction in Hepa[1,2,3,4,5,6] cells, with ER stress occurring before P300 induction
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