ABSTRACT
GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory-element-binding protein)-1c, LXRα (liver X receptor α) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra-/- mice and Chrebp-/- mice with S4048 demonstrated that ChREBP, but not LXRα, mediates the induction of hepatic lipogenic gene expression in this murine model of GSD-1. Thus ChREBP is an attractive target to alleviate derangements in lipid metabolism observed in patients with GSD-1.
Subject(s)
Gene Expression Regulation , Glycogen Storage Disease/genetics , Nuclear Proteins/deficiency , Transcription Factors/deficiency , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Cholesterol/metabolism , Disease Models, Animal , Glucose-6-Phosphatase/adverse effects , Glucose-6-Phosphatase/genetics , Glucose-6-Phosphatase/metabolism , Glycogen Storage Disease/enzymology , Glycogen Storage Disease/metabolism , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacology , Liver/enzymology , Liver/metabolism , Liver Glycogen/metabolism , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Orphan Nuclear Receptors/deficiency , Orphan Nuclear Receptors/genetics , Orphan Nuclear Receptors/metabolism , Pyridines/administration & dosage , Pyridines/pharmacology , RNA/genetics , RNA/isolation & purification , Transcription Factors/genetics , Transcription Factors/metabolism , Triglycerides/metabolismABSTRACT
Diabetes mellitus is a metabolic disorder affecting a great part of population around the world. It is the fifth leading death causing disease in the world and its cases are increasing day by day. Traditional medicine is thought to have promising future in the treatment of diabetes mellitus. In contrast to synthetic drugs phytochemicals are considered to be free from side effects. As one of the main class of natural products, alkaloids and their derivatives have been widely used as sources of pharmacological agents against a variety of medical problems. Many studies confirmed the role of alkaloids in the management of diabetes and numerous alkaloids isolated from different medicinal plants were found active against diabetes. Like other natural products, alkaloids regulate glucose metabolism either by inhibiting or inducing multiple candidate proteins including AMP-activated protein kinase, glucose transporters, glycogen synthase kinase-3, sterol regulatory element-binding proteins 1, glucokinase, glucose-6-phosphatase, acetyl-CoA carboxylase among the others. A comprehensive review of alkaloids reported in the literature with anti-diabetic activities and their target enzymes is conducted, with the aim to help in exploring the use of alkaloids as anti-diabetic agents. Future work should focus on rigorous clinical studies of the alkaloids, their development and relevant drug targets.