Dataset Information

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice.

ABSTRACT: The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mdm2, a protein that promotes p53 degradation, led to hepatocyte synthesis of connective tissue growth factor (CTGF; the hepatic fibrogenic master switch), increased hepatocyte apoptosis, and spontaneous liver fibrosis; concurrent removal of p53 completely abolished this phenotype. Compared with wild-type controls, mice with hepatocyte-specific p53 deletion exhibited similar levels of hepatocyte apoptosis but decreased liver fibrosis and hepatic CTGF expression in two models of liver fibrosis. The clinical significance of these data was highlighted by two observations. First, p53 upregulated CTGF in a human hepatocellular carcinoma cell line by repressing miR-17-92. Second, human liver samples showed a correlation between CTGF and p53-regulated gene expression, which were both increased in fibrotic livers. This study reveals that p53 induces CTGF expression and promotes liver fibrosis, suggesting that the p53/CTGF pathway may be a therapeutic target in the treatment of liver fibrosis.

SUBMITTER: Kodama T

PROVIDER: S-EPMC3148730 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice.

Kodama Takahiro T Takehara Tetsuo T Hikita Hayato H Shimizu Satoshi S Shigekawa Minoru M Tsunematsu Hinako H Li Wei W Miyagi Takuya T Hosui Atsushi A Tatsumi Tomohide T Ishida Hisashi H Kanto Tatsuya T Hiramatsu Naoki N Kubota Satoshi S Takigawa Masaharu M Tomimaru Yoshito Y Tomokuni Akira A Nagano Hiroaki H Doki Yuichiro Y Mori Masaki M Hayashi Norio N

The Journal of clinical investigation 20110711 8

The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mdm2, a protein that promotes p53 de ...[more]

PMID: 21747166

Similar Datasets

Project description:Liver fibrosis is the common outcome of many chronic liver diseases, resulting from altered cell-cell and cell-matrix interactions that promote hepatic stellate cell (HSC) activation and excessive matrix production. This study aimed to investigate functions of cellular communication network factor 2 (CCN2)/Connective tissue growth factor (CTGF), an extracellular signaling modulator of the CYR61/CTGF/Nov (CCN) family, in liver fibrosis. Tamoxifen-inducible conditional knockouts in mice and hepatocyte-specific deletion of this gene in rats were generated using the Cre-lox system. These animals were subjected to peri-central hepatocyte damage caused by carbon tetrachloride. Potential crosstalk of this molecule with a new profibrotic pathway mediated by the Slit2 ligand and Roundabout (Robo) receptors was also examined. We found that Ccn2/Ctgf was highly upregulated in periportal hepatocytes during carbon tetrachloride-induced hepatocyte damage, liver fibrosis and cirrhosis in mice and rats. Overexpression of this molecule was observed in human hepatocellular carcinoma (HCC) that were surrounded with fibrotic cords. Deletion of the Ccn2/Ctgf gene significantly reduced expression of fibrosis-related genes including Slit2, a smooth muscle actin (SMA) and Collagen type I during carbon tetrachloride-induced liver fibrosis in mice and rats. In addition, Ccn2/Ctgf and its truncated mutant carrying the first three domains were able to interact with the 7th -9th epidermal growth factor (EGF) repeats and the C-terminal cysteine knot (CT) motif of Slit2 protein in cultured HSC and fibrotic murine livers. Ectopic expression of Ccn2/Ctgf protein upregulated Slit2, promoted HSC activation, and potentiated fibrotic responses following chronic intoxication by carbon tetrachloride. Moreover, Ccn2/Ctgf and Slit2 synergistically enhanced activation of phosphatidylinositol 3-kinase (PI3K) and AKT in primary HSC, whereas soluble Robo1-Fc chimera protein could inhibit these activities. These observations demonstrate conserved cross-species functions of Ccn2/Ctgf protein in rodent livers. This protein can be induced in hepatocytes and contribute to liver fibrosis. Its novel connection with the Slit2/Robo signaling may have therapeutic implications against fibrosis in chronic liver disease.

Project description:Background & aimsIndividuals with alcohol use disorder (AUD) are at risk of liver disease. There is scarce information on the effectiveness of screening for liver fibrosis on alcohol consumption. Thus, we evaluated the efficacy of a screening program for liver fibrosis on alcohol consumption in individuals with AUD.MethodsWe performed a prospective interventional study in the Hospital Clinic of Barcelona. The screening cohort included individuals with AUD from the addiction unit who underwent screening for liver fibrosis with transient elastography and counselling on lifestyle habits in the liver unit. The control cohort included individuals with similar characteristics who attended the same unit in a previous period but did not undergo screening. Effects on alcohol consumption were evaluated at 6 months, after clinical follow-up, with clinical assessment by addiction specialists and urine ethyl glucuronide monitoring.ResultsIn the screening cohort, 149/334 (45%) individuals were abstinent at 6 months (68% confirmed with urine ethyl glucuronide). Alcohol abstinence was higher in the screening cohort than in the control cohort (40/137 [29%], p = 0.002). Factors associated with alcohol abstinence in the multivariate analysis of the two combined cohorts (n = 471) were: receiving AUD medications (odds ratio [OR] 1.72, 95% CI 1.11-2.67), absence of illicit drug use (OR 0.50, 95% CI 0.31-0.80) and participating in the screening program (OR 1.77, 95% CI 1.14-2.74). In the screening cohort, 40 (12%) individuals had increased liver stiffness (≥8 kPa), which was associated with obesity (p = 0.03), arterial hypertension (p = 0.03), gamma-glutamyltransferase (p <0.001) and platelet levels (p = 0.001).ConclusionsThis study shows that an integrated screening program for liver fibrosis associated with counselling on alcohol consumption in individuals with AUD allows for early diagnosis of alcohol-associated liver disease and is associated with alcohol abstinence.Impact and implicationsIndividuals with high alcohol consumption are at higher risk of liver disease compared to the general population. The potential beneficial effects of screening for liver disease in this population have scarcely been studied. We show that a screening program for liver fibrosis together with a lifestyle counselling intervention favoured alcohol abstinence among individuals with alcohol use disorder attending an addiction unit at 6 months, compared to a matched cohort who did not undergo screening. These findings suggest that screening programs for liver fibrosis have a therapeutic role in individuals with alcohol use disorder, supporting the implementation of these programs in addiction units.

Dataset Information

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice.

Publications

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets