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Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR?) is a key regulator of glucose and lipid metabolism. Agonists of this nuclear receptor are used in the treatment of type 2 diabetes and are also studied as a potential treatment of other metabolic diseases, including nonalcoholic fatty liver disease. Silymarin, a concentrated phenolic mixture from milk thistle (Silybum marianum) seeds, is used widely as a supportive agent in the treatment of a variety of liver diseases. In this study, the PPAR? activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPAR?-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPAR? antagonist T0070907. In silico docking studies suggested a binding mode for 3 distinct from that of the inactive silymarin constituents, with one additional hydrogen bond to Ser342 in the entrance region of the ligand-binding domain of the receptor. Hence, isosilybin A (3) has been identified as the first flavonolignan PPAR? agonist, suggesting its further investigation as a modulator of this nuclear receptor.

SUBMITTER: Pferschy-Wenzig EM

PROVIDER: S-EPMC4003856 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.

Pferschy-Wenzig Eva-Maria EM Atanasov Atanas G AG Malainer Clemens C Noha Stefan M SM Kunert Olaf O Schuster Daniela D Heiss Elke H EH Oberlies Nicholas H NH Wagner Hildebert H Bauer Rudolf R Dirsch Verena M VM

Journal of natural products 20140305 4

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism. Agonists of this nuclear receptor are used in the treatment of type 2 diabetes and are also studied as a potential treatment of other metabolic diseases, including nonalcoholic fatty liver disease. Silymarin, a concentrated phenolic mixture from milk thistle (Silybum marianum) seeds, is used widely as a supportive agent in the treatment of a variety of liver diseases. In this study, the P ...[more]

PMID: 24597776

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Project description:Apolipoprotein E (apoE) and its receptor, very low density lipoprotein receptor (VLDLR), are involved in fat accumulation in adipocytes. Here, we investigated the effect of a peroxisome proliferator-activated receptor (PPAR) gamma agonist, rosiglitazone, on regulation of VLDLR expression both in white adipose tissue (WAT) of obese mice and in cultured adipocytes. Furthermore, to determine whether rosiglitazone directly regulates transcription of the VLDLR gene, we carried out luciferase assay with a reporter gene containing mouse VLDLR promoter region, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Four-day treatment with rosiglitazone increased the expression of VLDLR in WAT of ob/ob mice. Moreover, rosiglitazone increased the expression of VLDLR in cultured adipocytes. The PPAR-responsive element (PPRE)-directed mutagenesis analyses revealed that the PPRE motif in the VLDLR promoter region plays a significant role in transcriptional activation of the VLDLR gene in adipocytes. In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that endogenous PPARgamma directly binds to this functional PPRE motif in the VLDLR promoter region. We also investigated the effects of rosiglitazone on insulin sensitivity and lipid accumulation in both ob/ob mice and apoE-deficient ob/ob mice. Rosiglitazone ameliorated insulin sensitivity in both ob/ob mice and apoE-deficient ob/ob mice, possibly through decreasing the expression of monocyte chemoattractant protein-1 (MCP-1), increasing the expression of superoxide dismutase 1 (SOD1) in WAT, and increasing plasma adiponectin concentration. In ob/ob mice, body weight and WAT weight were significantly higher in the mice treated with rosiglitazone than those treated with vehicle. However, in apoE-deficient ob/ob mice, no significant difference in body weight or WAT weight was observed between the vehicle-treated group and the rosiglitazone-treated group. Moreover, rosiglitazone did not increase body weight and WAT weight in VLDLR-deficient mice. These findings indicate that rosiglitazone directly increases VLDLR expression, thereby enhancing apoE-VLDLR-dependent lipid accumulation in adipocytes.

Dataset Information

Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.

Publications

Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.

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