Key result
Endothelial Egfr deficiency in type II diabetic mice upregulated MCP-1, leading to augmented monocyte recruitment, increased hepatic macrophages, and systemic glucose intolerance.
Why the study?
How liver endothelial cells regulate inflammation in the setting of insulin resistance remains unknown.
Does endothelial Egfr signaling reduce monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice?
Does endothelial Egfr signaling reduce monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice?
Endothelial Egfr signaling plays a protective role in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetes.
Endothelial Egfr may protect against hepatic inflammation in diabetic mice; hypothesis-generating for human translation.
Insulin resistance is a compromised response to insulin in target tissues such as liver. Emerging evidence shows that vascular endothelial cells (ECs) are critical in mediating glucose metabolism. However, how liver ECs can regulate inflammation in the setting of insulin resistance is still unknown. Using genome-wide transcriptome analysis of ECs isolated from diabetic mice, we found enrichment of the genes involved in epidermal growth factor receptor (Egfr) signaling. In line with this, hepatic sinusoidal ECs in diabetic mice had elevated levels of Egfr expression. Interestingly, we found an increased number of hepatic myeloid cells, especially macrophages, and systemic glucose intolerance in Cdh5Cre/+Egfrfl/fl mice lacking Egfr in ECs compared with littermate control mice with type II diabetes. Egfr deficiency upregulated the expression of MCP-1 in hepatic sinusoidal ECs. This resulted in augmented monocyte recruitment and macrophage differentiation in Cdh5Cre/+Egfrfl/fl mice compared with littermate control mice as determined by a mouse model of parabiosis. Finally, MCP-1 neutralization and hepatic macrophage depletion in Cdh5Cre/+Egfrfl/fl mice resulted in a reduced number of hepatic macrophages and ameliorated glucose intolerance compared with the control groups. Collectively, these results demonstrate a protective endothelial Egfr signaling in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice.
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Zhang et al. (2023) studied Type II diabetes and insulin resistance. Endothelial Egfr deficiency vs. Littermate control mice with type II diabetes was evaluated on Hepatic myeloid cell recruitment, macrophage differentiation, and systemic glucose intolerance. Endothelial Egfr deficiency in type II diabetic mice upregulated MCP-1, leading to augmented monocyte recruitment, increased hepatic macrophages, and systemic glucose intolerance.
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