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      Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

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          Abstract

          Triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., exerts a unique bioactive spectrum of anti-inflammatory and anticancer activities. However, triptolide’s clinical applications are limited due to its severe toxicities. Fatty liver toxicity occurs in response to triptolide, and this toxic response significantly differs between males and females. This report investigated the pathogenesis underlying the sex-related differences in the dyslipidosis induced by triptolide in rats. Wistar rats were administered 0, 150, 300, or 450 μg triptolide/kg/day by gavage for 28 days. Ultrastructural examination revealed that more lipid droplets were present in female triptolide-treated rats than in male triptolide-treated rats. Furthermore, liver triglyceride, total bile acid and free fatty acid levels were significantly increased in female rats in the 300 and 450 μg/kg dose groups. The expression of liver X receptor α (LXRα) and its target genes, cholesterol 7α-hydroxylase (CYP7A1) and Sterol regulatory element-binding transcription factor 1(SREBP-1), increased following triptolide treatment in both male and female rats; however, the female rats were more sensitive to triptolide than the male rats. In addition, the expression of acetyl-CoA carboxylase 1(ACC1), a target gene of SREBP-1, increased in the female rats treated with 450 μg triptolide/kg/day, and ACC1 expression contributed to the sex-related differences in the triptolide-induced dysfunction of lipid metabolism. Our results demonstrate that the sex-related differences in LXR/SREBP-1-mediated regulation of gene expression in rats are responsible for the sex-related differences in lipid metabolism induced by triptolide, which likely underlie the sex-related differences in triptolide hepatotoxicity. This study will be important for predicting sex-related effects on the pharmacokinetics and toxicity of triptolide and for improving its safety.

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          Most cited references41

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          Bile acid receptors as targets for drug development.

          The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.
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            Bile acids are nutrient signaling hormones.

            Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-α target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCζ, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2.
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              Sex differences in the metabolic syndrome: implications for cardiovascular health in women.

              The metabolic syndrome is a clinical condition characterized by the presence of multiple interrelated risk factors for type 2 diabetes and cardiovascular disease. Component features include dysglycemia, increased blood pressure, increased triglycerides, decreased HDL cholesterol concentrations, and obesity (in particular, abdominal obesity). The underlying biology, optimal diagnostic criteria, and clinical implications, once diagnosed, have been matter for intense debate. Despite these areas of controversy, there is now general consensus that the observed risk factor clustering signifies heightened cardiovascular risk. The influence of sex on the clinical expression and pathophysiology of the syndrome is underrecognized, and is an issue of increasing importance given the alarming increase in prevalence among young women. This minireview will highlight sex differences in the epidemiology, etiology, biology, and clinical expression of the metabolic syndrome. In particular, key sex differences include distinctions in (a) prevalence of dysglycemia, (b) body fat distribution, (c) adipocyte size and function, (d) hormonal regulation of body weight and adiposity, and (e) the influence of estrogen decline on risk factor clustering. Accumulated and emerging data convincingly demonstrate that significant heterogeneity exists between men and women developing the metabolic syndrome, in large part related to hormonal regulation of body fat distribution and attendant metabolic abnormalities.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                31 March 2016
                2016
                : 7
                : 87
                Affiliations
                [1] 1Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University Nanjing, China
                [2] 2Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University Nanjing, China
                [3] 3State Key Laboratory of Natural Medicines, China Pharmaceutical University Nanjing, China
                [4] 4Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University Nanjing, China
                Author notes

                Edited by: Adolfo Andrade-Cetto, Universidad Nacional Autónoma de México, Mexico

                Reviewed by: Ru Yan, University of Macau, China; Biswapriya Biswavas Misra, University of Florida, USA

                *Correspondence: Luyong Zhang, yzhang@ 123456cpu.edu.cn ; Lixin Sun, slxcpu@ 123456126.com

                These authors have contributed equally to this work.

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2016.00087
                4814849
                27065871
                841ea728-786a-4c1d-ab99-4cef761e139a
                Copyright © 2016 Jiang, Huang, Huang, Guo, Wang, Li, Huang, Wang, Zhang and Sun.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 December 2015
                : 16 March 2016
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 46, Pages: 10, Words: 0
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                triptolide,hepatotoxicity,lipid metabolism,liver x receptor α,sterol regulatory element-binding transcription factor 1

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