title: Alleviation of high-fat diet-induced atherosclerosis and glucose intolerance by a novel GLP-1 fusion protein in ApoE(-/-) mice.
abstract: We have previously constructed an engineered anti-diabetic fusion protein using glucagon-like peptide-1 and the globular domain of adiponectin. Herein, we evaluated the therapeutic effects of this fusion protein (GAD) on high-fat diet (HFD)-fed ApoE(-/-) mice. The lipid-lowering effect of GAD was determined in C57BL/6 mice using a lipid tolerance test. The effects of GAD on HFD-induced glucose intolerance, atherosclerosis, and hepatic steatosis were evaluated in HFD-fed ApoE(-/-) mice using glucose tolerance test, histological examinations and real-time quantitative PCR. The anti-inflammation activity of GAD was assessed in vitro on macrophages. GAD improved lipid metabolism in C57BL/6 mice. GAD treatment alleviated glucose intolerance, reduced blood lipid level, and attenuated atherosclerotic lesion in HFD-fed ApoE(-/-) mice, which was associated with a repressed macrophage infiltration in the vessel wall. GAD treatment also blocked hepatic macrophage infiltration and prevented hepatic inflammation. GAD suppressed lipopolysaccharide-triggered inflammation responses on macrophages, which can be abolished by H89, an inhibitor of protein kinase A. These findings demonstrate that GAD is able to generate a variety of metabolic benefits in HFD-fed ApoE(-/-) mice and indicate that this engineered fusion protein is a promising lead structure for anti-atherosclerosis drug discovery.
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Kong
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Tong
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
authors.forename: Mingming
authors.initials: M
authors.lastname: Gao
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China. xdgao@cpu.edu.cn.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Gao
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China. wbyao@cpu.edu.cn.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Yao
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D052216:Glucagon-Like Peptide 1
keywords: Adiponectin; Atherosclerosis; Glucagon-like peptide-1; Lipid metabolism
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