title: Kukoamine A attenuates insulin resistance and fatty liver through downregulation of Srebp-1c.
abstract: Nonalcoholic fatty liver disease (NAFLD) refers to a pathological condition of hepatic steatosis. Insulin resistance is believed to be the key mechanism mediating initial accumulation of fat in the liver, resulting in hepatic steatosis. Kukoamine A (KuA), a spermine alkaloid, is a major bioactive component extracted from the root barks of Lycium chinense (L. chinense) Miller. In the current study, we aimed to explore the possible effect of KuA on insulin resistance and fatty liver. We showed that KuA significantly inhibited the increase of fasting blood glucose level and insulin level, and the glucose levels in response to glucose and insulin load in HFD-fed mice, which was in a dose-dependent manner. KuA dose-dependently decreased the histological injury of liver, levels of hepatic triglyceride (TG), and serum AST and ALT activities in HFD-fed mice. The increase of serum levels of TNFɑ, IL-1β, IL-6 and C reactive protein in HFD-fed mice was inhibited by KuA. HFD feeding-induced increase of hepatic expression of Srebp-1c and its target genes, including fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1), was significantly inhibited by KuA. Moreover, upregulation of Srebp-1c notably inhibited KuA-induced improvement of insulin-stimulated glucose uptake, decrease of lipid accumulation and H2O2level in palmitic acid-treated AML-12 cells. In conclusion, we reported that KuA inhibited Srebp-1c and downstream genes expression and resulted in inhibition of lipid accumulation, inflammation, insulin resistance and oxidative stress. Overall, our results provide a better understanding of the pharmacological activities of KuA against insulin resistance and hepatic steatosis.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China. Electronic address: Lguangyun123@163.com.
authors.forename: Guangyun
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D007333:Insulin Resistance; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C096274:kukoamine A; D013096:Spermine
keywords: Fatty liver; Insulin resistance; Kukoamine A; Oxidative stress; Srebp-1c