Alteration in body composition in the portacaval anastamosis rat is mediated by increased expression of myostatin

Abstract

AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) 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-α and PPAR-γ 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-α activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-γ were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-γ activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-α (RAR-α), 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-α 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-α subunits. Expression of either a constitutively active or dominant negative AMPK-α inhibited basal and WY-14,643-stimulated PPAR-α activity and basal and rosiglitazone-stimulated PPAR-γ activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-α and PPAR-γ, 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-α and -γ may allow for short-term processes to increase energy generation before the cells devote resources to increasing their capacity for fatty acid oxidation.

Involvement of PPARγ in the antitumoral action of cannabinoids on hepatocellular carcinoma

“…Our results are in contrast with recent research showing that activation of AMPK inhibits transcriptional activity of PPAR γ in HepG2 cells. 34 However, in this study, the effects of AMPK did not appear to be mediated through effects on PPAR γ binding to DNA and were independent of the kinase activity. 34 …”

Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit?

“…Blocking myostatin not only increases muscle mass but also protects mice from fatty liver and improves insulin resistance (16,17). Furthermore, myostatin also promotes an increase in muscle mass depending on the time of exposure of adipocytes in their development (18). Myostatin receptor, Activin IIbr, has been reported, albeit in abstract form only, in hepatic stellate cells.…”

Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα

“…Although a direct interaction between PPARα and AMPK was observed before (69), the influence of AMPK activation on PPARα activity is still not completely clear. AMPK was shown to co-activate PPARα in an inactive ATP-bound state (69,70) but the effects of pharmacological AMPK activation on PPARα activity are contradictory, showing both inhibition (69,70) and activation (71). Similarly, GCs can activate liver AMPK (52) and pharmacological AMPK activation was shown to alter the effects of glucocorticoids on liver carbohydrate metabolism (13), however, via an indirect mechanism, involving p38 MAPK activation.…”