TY - JOUR
T1 - Adiponectin regulation of stellate cell activation via PPARγ- dependent and -independent mechanisms
AU - Shafiei, Mahnoush S.
AU - Shetty, Shoba
AU - Scherer, Philipp E.
AU - Rockey, Don C.
N1 - Funding Information:
Supported by the NIH (R01-DK50574 to D.C.R.; and R01-DK55758, R01-CA112023, RC1-DK086629, and P01-DK088761 to P.E.S.).
PY - 2011/6
Y1 - 2011/6
N2 - In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin- null animals developed severe fibrosis. Expression of collagen σ1(I) and σ-smooth muscle actin (σ-SMA) mRNAs were significantly lower in adiponectin- overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator- activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed upregulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an ade-novirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells.
AB - In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin- null animals developed severe fibrosis. Expression of collagen σ1(I) and σ-smooth muscle actin (σ-SMA) mRNAs were significantly lower in adiponectin- overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator- activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed upregulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an ade-novirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells.
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U2 - 10.1016/j.ajpath.2011.02.035
DO - 10.1016/j.ajpath.2011.02.035
M3 - Article
C2 - 21641391
AN - SCOPUS:79959439461
SN - 0002-9440
VL - 178
SP - 2690
EP - 2699
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -