The orphan nuclear receptor small heterodimer partner is required for thiazolidinedione effects in leptin-deficient mice.
Animals; Bile Acids and Salts/metabolism; Cytoplasmic and Nuclear/biosynthesis/*genetics/metabolism; Diabetes Mellitus/*drug therapy/genetics/metabolism; Gene Expression Regulation/drug effects; Glucose/metabolism; Hepatocytes/drug effects; Humans; Insulin Resistance/genetics; Insulin/*metabolism; Leptin/deficiency/genetics; Lipid Metabolism/drug effects; Messenger/genetics; Mice; Obese; PPAR gamma/*biosynthesis/genetics; Receptors; RNA; Thiazolidinediones/*administration & dosage
BACKGROUND: Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp(-/-)) double mutant mice. RESULTS: Both ob/ob and double mutant ob/ob;Shp(-/-) mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp(-/-) mice. PPARgamma2 mRNA levels were markedly lower in ob/ob;Shp(-/-) liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp(-/-) mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp(-/-) mice. Moreover, overexpression of SHP by adenovirus infection increased PPARgamma2 mRNA levels in mouse primary hepatocytes. CONCLUSIONS: Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARgamma expression.
Tseng Hsiu-Ting; Park Young Joo; Lee Yoon-Kwang; Moore David D
Journal of biomedical science
2015
2015-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12929-015-0133-3" target="_blank" rel="noreferrer noopener">10.1186/s12929-015-0133-3</a>
Bile acid receptors in non-alcoholic fatty liver disease.
Animals; Bile Acids and Salts/*metabolism; Cholesterol; Cytoplasmic and Nuclear/agonists/*metabolism; Fatty Liver/drug therapy/immunology/*metabolism; FXR; G-Protein-Coupled/agonists/*metabolism; Glucose/metabolism; Humans; Inflammation; Lipid Metabolism/drug effects; Lipid Regulating Agents/chemistry/pharmacology/therapeutic use; Molecular Structure; Non-alcoholic Fatty Liver Disease; Receptors; TGR5; Triglyceride; Triglycerides/metabolism
Accumulating data have shown that bile acids are important cell signaling molecules, which may activate several signaling pathways to regulate biological processes. Bile acids are endogenous ligands for the farnesoid X receptor (FXR) and TGR5, a G-protein coupled receptor. Gain- and loss-of-function studies have demonstrated that both FXR and TGR5 play important roles in regulating lipid and carbohydrate metabolism and inflammatory responses. Importantly, activation of FXR or TGR5 lowers hepatic triglyceride levels and inhibits inflammation. Such properties of FXR or TGR5 have indicated that these two bile acid receptors are ideal targets for treatment of non-alcoholic fatty liver disease, one of the major health concerns worldwide. In this article, we will focus on recent advances on the role of both FXR and TGR5 in regulating hepatic triglyceride metabolism and inflammatory responses under normal and disease conditions.
Li Yuanyuan; Jadhav Kavita; Zhang Yanqiao
Biochemical pharmacology
2013
2013-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bcp.2013.08.015" target="_blank" rel="noreferrer noopener">10.1016/j.bcp.2013.08.015</a>