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Q Li, Tokushima, Japan
W Yin, University of South China, Hunan , China
M Cai, Institute of Cardiovascular, University of South China, Hunan, China
Y Liu, Institute of Cardiovascular Research, University of South China, Hunan, China
H Hou, Institute of Cardiovascular Research, University of South China, Hunan, China
Q Shen, Institute of Cardiovascular Research, University of South China, Hunan, China
C Zhang, Institute of Cardiovascular Research, University of South China, Hunan, China
J Xiao, Institute of Cardiovascular Research, University of South China, Hunan, China
X Hu, Institute of Cardiovascular Research, University of South China, Hunan, China
Q Wu, 2Department of Nutrition and Metabolism, University of Tokushima, Tokushima, Japan
M Funaki, Clinical Research Center for Diabetes, University of Tokushima, Tokushima, Japan
Y Nakaya, 2Department of Nutrition and Metabolism, University of Tokushima, Tokushima, Japan

Qinkai Li, Email: lqk617{at}yahoo.co.jp

Insulin resistance and dyslipidaemia are both involved into the risk factors of metabolic syndrome. Low levels of insulin-like growth factor 1 (IGF-1) are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver functions to secret IGF-1 and catabolize cholesterol regulated by the rate limiting enzyme of bile acid synthesis from cholesterol 7-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase (LPL) activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF-1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF-1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF-1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF-1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886, recovered hyperinsulinemia and low plasma levels of IGF-1, suppressed LDL-C and facilitated RCT by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/ high-sucrose/ high-cholesterol diet (HFSCD) minipigs. These findings indicate that NO-1886 upregulates IGF-1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 on T2DM and metabolic syndrome.