Adiponectin regulation of stellate cell activation via PPARγ- dependent and -independent mechanisms

Mahnoush S. Shafiei, Shoba Shetty, Philipp E. Scherer, Don C. Rockey

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2690-2699
Number of pages10
JournalAmerican Journal of Pathology
Volume178
Issue number6
DOIs
StatePublished - Jun 2011

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Peroxisome Proliferator-Activated Receptors
Adiponectin
troglitazone
Collagen
Messenger RNA
Fibrosis
Thioacetamide
Hepatic Stellate Cells
Null Lymphocytes
Lentivirus
Transgenic Mice
Transcriptional Activation
Smooth Muscle
Actins
Up-Regulation
Viruses

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Adiponectin regulation of stellate cell activation via PPARγ- dependent and -independent mechanisms. / Shafiei, Mahnoush S.; Shetty, Shoba; Scherer, Philipp E.; Rockey, Don C.

In: American Journal of Pathology, Vol. 178, No. 6, 06.2011, p. 2690-2699.

Research output: Contribution to journalArticle

Shafiei, Mahnoush S. ; Shetty, Shoba ; Scherer, Philipp E. ; Rockey, Don C. / Adiponectin regulation of stellate cell activation via PPARγ- dependent and -independent mechanisms. In: American Journal of Pathology. 2011 ; Vol. 178, No. 6. pp. 2690-2699.
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