Hepatocyte-specific Prominin-1 protects against liver injury-induced fibrosis by stabilizing SMAD7

Abstract

Prominin-1 (PROM1), also known as CD133, is expressed in hepatic progenitor cells (HPCs) and cholangiocytes of the fibrotic liver. In this study, we show that PROM1 is upregulated in the plasma membrane of fibrotic hepatocytes. Hepatocellular expression of PROM1 was also demonstrated in mice (Prom1(CreER); R26(TdTom)) in which cells expressed TdTom under control of the Prom1 promoter. To understand the role of hepatocellular PROM1 in liver fibrosis, global and liver-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL). BDL-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased levels of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that hepatocyte-specific overexpression of SMAD7 ameliorated BDL-induced liver fibrosis in liver-specific Prom1-deficient mice. Thus, we conclude that PROM1 is necessary for the negative regulation of TGF beta signaling during liver fibrosis. Liver disease: Preventing progression of fibrosis Progression of liver fibrosis is kept in check by a regulatory protein that switches off a signaling pathway responsible for cell death and subsequent scar tissue formation. Liver fibrosis is a common outcome of alcoholism, viral infection, and hepatitis. Researchers led by Young-Gyu Ko at Korea University, Seoul, South Korea, determined that a protein called PROM-1 is highly expressed in fibrotic liver tissue from mice and humans, and set out to uncover its function. They found that PROM-1 exerts a protective role, as PROM-1-deficient mice experienced accelerated liver degeneration in response to bile duct injury. PROM-1 acts by blocking the effects of transforming growth factor-beta, a signaling protein which promotes cell death. These results are consistent with evidence linking PROM-1 to anti-fibrotic activity in other organ systems.