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

Prominin-1 (PROM1), also known as CD133, is known to be expressed in hepatic progenitor cells (HPCs) and cholangiocytes of fibrotic liver. In this study, we show that PROM1 was upregulated in the plasma membranes of fibrotic hepatocytes. The hepatocellular expression of PROM1 was also demonstrated in the mice (Prom1CreER; R26TdTom) where cells express TdTom under the control of Prom1 promoter. To understand the role of hepatocellular PROM1 on liver fibrosis, global and liver- and cholangiocyte-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treatment. BDL- and CCl4-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased level 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...