Activated AMPK inhibits PPAR-alpha and PPAR-gamma transcriptional activity in hepatoma cells

作者：Sozio Margaret S^*; Lu Changyue; Zeng Yan; Liangpunsakul Suthat; Crabb David W

来源：American Journal of Physiology - Gastrointestinal and Liver Physiology, 2011, 301(4): G739-G747.

DOI：10.1152/ajpgi.00432.2010

• nuclear receptors
• fatty acid oxidation
• compound C
• AMP-activated protein kinase
• peroxisome proliferator-activated receptor

Sozio MS, Lu C, Zeng Y, Liangpunsakul S, Crabb DW. Activated AMPK inhibits PPAR-alpha and PPAR-gamma transcriptional activity in hepatoma cells. Am J Physiol Gastrointest Liver Physiol 301: G739-G747, 2011. First published June 23, 2011; doi: 10.1152/ajpgi.00432.2010.-AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) are critical regulators of short-term and long-term fatty acid oxidation, respectively. We examined whether the activities of these molecules were coordinately regulated. H4IIEC3 cells were transfected with PPAR-alpha and PPAR-gamma expression plasmids and a peroxisome-proliferator-response element (PPRE) luciferase reporter plasmid. The cells were treated with PPAR agonists (WY-14,643 and rosiglitazone), AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAR) and metformin, and the AMPK inhibitor compound C. Both AICAR and metformin decreased basal and WY-14,643-stimulated PPAR-gamma activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-gamma were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-gamma activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-alpha (RAR-alpha), another nuclear receptor that dimerizes with retinoid X receptor (RXR), was largely unaffected by the AMPK activators. Compound C modestly increased AM580 (an RAR agonist)-stimulated activity. The AMPK activators did not affect PPAR-alpha binding to DNA, and there was no consistent correlation between effects of the AMPK activators and inhibitor on PPAR and the nuclear localization of AMPK-alpha subunits. Expression of either a constitutively active or dominant negative AMPK-alpha inhibited basal and WY-14,643-stimulated PPAR-alpha activity and basal and rosiglitazone-stimulated PPAR-gamma activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-alpha and PPAR-gamma, whereas inhibition of AMPK with compound C activated both PPARs. The effects of AMPK do not appear to be mediated through effects on RXR or on PPAR/RXR binding to DNA. These effects are independent of kinase activity and instead appear to rely on the activated conformation of AMPK. AMPK inhibition of PPAR-alpha and -gamma may allow for short-term processes to increase energy generation before the cells devote resources to increasing their capacity for fatty acid oxidation.

• 出版日期2011-10