Abstract
Mitogen-inducible gene 6 (Mig-6) is a negative feedback inhibitor of epidermal growth factor receptor (EGFR) signaling. We previously found that Mig-6 plays a critical role in the regulation of cholesterol homeostasis and in bile acid synthesis. In this study, we investigated the effects of EGFR inhibition to identify a potential new treatment target for hypercholesterolemia. We used a mouse model with conditional ablation of the Mig-6 gene in the liver (Albcre/+Mig-6f/f; Mig-6d/d) to effectively investigate the role of Mig-6 in the regulation of liver function. Mig-6d/d mice were treated with either the EGFR inhibitor gefitinib or statin for 6 weeks after administration of a high-fat or standard diet. We then compared lipid profiles and other parameters among each group of mice. After a high-fat diet, Mig-6d/d mice showed elevated serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and glucose, characteristics resembling hypercholesterolemia in diabetic patients. We observed decreases in serum levels of lipids and glucose in high-fat-diet-fed Mig-6d/d mice after 6 weeks of treatment with gefitinib or statin. Furthermore gefitinib-treated mice showed significantly greater decreases in serum levels of total, HDL and LDL cholesterol compared with statin-treated mice. Taken together, these results suggest that EGFR inhibition is effective for the treatment of hypercholesterolemia in high-fat-diet-fed Mig-6d/d mice, and our findings provide new insights into the development of possible treatment targets for hypercholesterolemia via modulation of EGFR inhibition.
Highlights
Hypercholesterolemia and dyslipidemia are common risk factors for cardiovascular disease, which is a leading cause of illness and death worldwide
We found that the Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib improved hypercholesterolemia and insulin resistance in high-fat-diet-fed Mig-6d/d mice
We examined the level of liver enzymes after gefitinib or statin treatment to evaluate the side effect of the both drugs on Mig-6d/d mice
Summary
Hypercholesterolemia and dyslipidemia are common risk factors for cardiovascular disease, which is a leading cause of illness and death worldwide. In the majority of people with hypercholesterolemia among the general public, the condition is attributable to a high-fat diet and to poorly understood susceptibility and modifier genes. Defining the molecular mechanisms regulating cholesterol homeostasis will lead to more effective methods of treating and preventing cardiovascular disease [1]. Statins have been the drugs of choice for decreasing plasma cholesterol levels, leading to substantial improvements in cardiovascular morbidity and mortality. Epidermal growth factor receptor (EGFR) signaling controls morphogenesis and/or homeostasis processes, including survival, proliferation, migration, and differentiation, in several tissues. Because of the capacity of EGFR signaling to promote numerous critical biological outcomes, dysregulation of this pathway has been implicated in many human diseases [3, 4]. Mitogen-inducible gene 6 (Mig-6) is an immediate early response gene encoding a non-kinase scaffolding adaptor protein induced by various mitogens, stressors and hormones that acts as a negative feedback inhibitor of EGFR signaling through its direct, physical interaction with EGFR [5,6,7]
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