NO-1886 suppresses diet-induced insulin resistance and cholesterol accumulation through STAT5-dependent upregulation of IGF1 and CYP7A1

• Published in: Journal of endocrinology Vol. 204; no. 1; pp. 47 - 56
• Main Authors: Li, Qinkai, Yin, Weidong, Cai, Manbo, Liu, Yi, Hou, Hongjie, Shen, Qingyun, Zhang, Chi, Xiao, Junxia, Hu, Xiaobo, Wu, Qishisan, Funaki, Makoto, Nakaya, Yutaka
• Format: Journal Article
• Language: English
• Published: England BioScientifica 01.01.2010
• Subjects: Animal Feed; Animals; Benzamides - administration & dosage; Benzamides - pharmacology; Cell Line, Tumor; Cholesterol - administration & dosage; Cholesterol - metabolism; Cholesterol 7-alpha-Hydroxylase - metabolism; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Dietary Fats - administration & dosage; Drug Administration Schedule; Humans; Hyperglycemia - etiology; Hyperglycemia - prevention & control; Hyperinsulinism - blood; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - pharmacology; Insulin Resistance; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - secretion; Liver - metabolism; Male; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - pharmacology; Regular papers; STAT5 Transcription Factor - metabolism; Swine; Swine, Miniature; Up-Regulation
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/JOE-09-0278

Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 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 secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7α-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase 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 IGF1 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 IGF1 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 IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.