title: NO-1886 suppresses diet-induced insulin resistance and cholesterol accumulation through STAT5-dependent upregulation of IGF1 and CYP7A1.
abstract: 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 7alpha-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.
authors.affiliation: Key Laboratory for Atherosclerology of Hunan Province, Institute of Cardiovascular Research, Life Science Research Center, University of South China, Hengyang, Hunan 421001, People's Republic of China.
authors.forename: Qinkai
authors.initials: Q
authors.lastname: Li
authors.forename: Weidong
authors.initials: W
authors.lastname: Yin
authors.forename: Manbo
authors.initials: M
authors.lastname: Cai
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongjie
authors.initials: H
authors.lastname: Hou
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Shen
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Junxia
authors.initials: J
authors.lastname: Xiao
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Hu
authors.forename: Qishisan
authors.initials: Q
authors.lastname: Wu
authors.forename: Makoto
authors.initials: M
authors.lastname: Funaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
mesh_terms: D000821:Animal Feed; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage; D004334:Drug Administration Schedule; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology / Q000517:prevention & control; D006946:Hyperinsulinism / Q000097:blood; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature; D015854:Up-Regulation
chemical_list: D001549:Benzamides; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D009943:Organophosphorus Compounds; D050799:STAT5 Transcription Factor; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase