PPAR? Is Required for PPAR? Action in Regulation of Body Weight and Hepatic Steatosis in Mice

[摘要] Peroxisome proliferator activated receptors alpha (PPAR?) and delta (PPAR?) belong to the nuclear receptor superfamily. PPAR? is a target of well established lipid-lowering drugs. PPAR? (also known as PPAR?/?) has been investigated as a promising antidiabetic drug target; however, the evidence in the literature on PPAR? effect on hepatic lipid metabolism is inconsistent. Mice conditionally expressing human PPAR? demonstrated pronounced weight loss and promoted hepatic steatosis when treated with GW501516 (PPAR?-agonist) when compared to wild type mice. This effect was completely absent in mice with either a dominant negative form of PPAR? or deletion of the DNA binding domain of PPAR?. This confirmed the absolute requirement for PPAR? in the physiological actions of GW501516 and confirmed the potential utility against the human form of this receptor. Surprisingly the genetic deletion of PPAR? also abrogated the effect of GW501516 in terms of both weight loss and hepatic lipid accumulation. Also the levels of the PPAR? endogenous agonist 16:0/18:1-GPC were shown to be modulated by PPAR? in wild type mice. Our results show that both PPAR? and PPAR? receptors are essential for GW501516-driven adipose tissue reduction and subsequently hepatic steatosis, with PPAR? working downstream of PPAR?.

[学科分类] 生物化学/生物物理