Abstract
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 PPARγ activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPARγ 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 PPARγ agonist, suggesting its further investigation as a modulator of this nuclear receptor.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors orchestrating the expression of genes relevant to lipid and glucose metabolism and occur in three isoforms, alpha, beta, and gamma.[1−3] PPAR type gamma (PPARγ) is most highly expressed in the adipose tissue, but important functional expression of this receptor has been allocated to a variety of nonadipose tissues and cell types, such as skeletal muscle, liver, pancreatic beta cells, myeloid dendritic cells, and macrophages.[4]
This ligand type demonstrates a range of undesirable side effects,[7] prompting the search for new PPARγ agonists effective in the context of lipid and glucose metabolism and inflammation
Article play a role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and can serve as targets for its therapy.[14−16] PPARs are key modulators of gene expression and hepatic triglyceride accumulation, and PPARγ agonists have shown promising results in clinical studies dealing with the treatment of NAFLD, more evidence for their efficacy from larger clinical studies is still needed.[11,12,17]
Summary
Article play a role in the pathogenesis of NAFLD and can serve as targets for its therapy.[14−16] PPARs are key modulators of gene expression and hepatic triglyceride accumulation, and PPARγ agonists have shown promising results in clinical studies dealing with the treatment of NAFLD, more evidence for their efficacy from larger clinical studies is still needed.[11,12,17]. The major part (typically 70−80%) of silymarin consists of seven flavonolignans (i.e., silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin; 1−6) and the flavonoid taxifolin (7).[23] Silybins A and B (1 and 2) and isosilybins A and B (3 and 4) are two regioisomeric pairs of diastereomers. Even though they were first described in the. Considering the relevant hepatotherapeutic traditional use of silymarin, as well as the existing interest in identification of novel PPARγ ligands, in this study it was aimed to investigate whether silymarin and its purified flavonolignan and flavonoid constituents are able to activate PPARγ
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