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Caveolin-1 abrogates TGF-? mediated hepatocyte apoptosis.

ABSTRACT: Transforming growth factor (TGF)-? has a dual role in liver, providing cytostatic effects during liver damage and regeneration, as well as carcinogenic functions in malignant transformation and hepatocellular cancer. In cultured hepatocytes, TGF-? can trigger apoptosis and epithelial-mesenchymal transition (EMT). Caveolin-1 is associated with progression of hepatocellular cancer and has been linked to TGF-? signaling. This study aimed at elucidating whether Caveolin-1 regulates TGF-? mediated hepatocyte fate. Knockdown of Caveolin-1 strongly reduced TGF-? mediated AKT phosphorylation, thus sensitized primary murine hepatocytes for proapoptotic TGF-? signaling. Restoration of AKT activity in Caveolin-1 knockdown cells via expression of a constitutive active AKT mutant did not completely blunt the apoptotic response to TGF-?, indicating an additional mechanism how Caveolin-1 primes hepatocytes for resistance to TGF-? triggered apoptosis. On the molecular level, Caveolin-1 interfered with TGF-? initiated expression of the proapoptotic mediator BIM. Additionally, RNAi for Caveolin-1 reduced (and its overexpression increased) expression of antiapoptotic mediators BCL-2 and BCL-xl. Noteworthy, reduced Caveolin-1 protein levels had no effect on collagen 1?1, E- and N-cadherin expression upon TGF-? challenge and thus no effect on hepatocyte EMT. Hence, via affecting TGF-? mediated non-Smad AKT signaling and regulation of pro- and antiapoptotic factors, Caveolin-1 is a crucial hepatocyte fate determinant for TGF-? effects.

SUBMITTER: Meyer C

PROVIDER: S-EPMC3563992 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis.

Meyer C C Liu Y Y Kaul A A Peipe I I Dooley S S

Cell death & disease 20130117

Transforming growth factor (TGF)-β has a dual role in liver, providing cytostatic effects during liver damage and regeneration, as well as carcinogenic functions in malignant transformation and hepatocellular cancer. In cultured hepatocytes, TGF-β can trigger apoptosis and epithelial-mesenchymal transition (EMT). Caveolin-1 is associated with progression of hepatocellular cancer and has been linked to TGF-β signaling. This study aimed at elucidating whether Caveolin-1 regulates TGF-β mediated he ...[more]

PMID: 23328673

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Project description:Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Dataset Information

Caveolin-1 abrogates TGF-? mediated hepatocyte apoptosis.

Publications

Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis.

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