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Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists down-regulate alpha2-macroglobulin expression by a PPARalpha-dependent mechanism.
Citation:
Gonzalez, M., C. CORTON, R. C. Cattley, E. Herrera, AND C. Bocos. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists down-regulate alpha2-macroglobulin expression by a PPARalpha-dependent mechanism. Biochimie. ELSEVIER, AMSTERDAM, Holland, 91(8):1029-1035, (2009).
Impact/Purpose:
Further information about the pathways activated in the livers of pregnant animals is necessary to determine the impact of inflammation on gene expression and if there are treatments that can down-regulate the inflammation.
Description:
Peroxisome proliferator-activated receptor alpha (PPARα) regulates transcription of genes involved both in lipid and glucose metabolism as well as inflammation. Fibrates are PPARα ligands used to normalize lipid and glucose parameters and exert anti-inflammatory effects. Fibrates have been demonstrated to benefit metabolic syndrome, type 2 diabetes and cardiovascular diseases. The acute phase response (APR) is an important inflammatory process. One of the most important acute phase proteins in rats is α2-macroglobulin (A2Mg). Whereas normal adult rats present low serum levels, pregnant rats display high amounts. Therefore, we used pregnant rats to detect the effect of fenofibrate on hepatic A2Mg expression by RT-PCR and Northern blot. Virgin rats were used as controls. The expression of other APR genes, a known fibrate-responder gene, gamma-chain fibrinogen (γ-Fib), and one gene from the same family as A2Mg, complement component 3 (C3), were also measured in liver. In order to determine whether the fibrate-effects were mediated by PPARα, wild type mice and PPARα-null mice were also used and treated with WY-14,643 (WY) or di-2-ethylhexyl phthalate (DEHP). Fenofibrate depressed A2Mg expression in virgin rats, but increased sharply, in pregnant rats. However, C3 and γ-Fib expression were diminished after the treatment only in pregnant rats. On the other hand, WY, but not DEHP, reduced A2Mg and γ-Fib expression in the livers of wild-type mice, without any effect in PPARα-null mice. WY or DEHP did not affect C3 expression. Therefore, A2Mg expression is modified by PPARα agonists both in rats and mice and A2Mg is a novel PPARα agonist-regulated gene.