RESUMEN
BACKGROUND & AIMS: Hepatic fibrosis is characterized by enhanced deposition of extracellular matrix (ECM), which results from the wound healing response to chronic, repeated injury of any etiology. Upon injury, hepatic stellate cells (HSCs) activate and secrete ECM proteins, forming scar tissue, which leads to liver dysfunction. Monocyte-chemoattractant protein-induced protein 1 (MCPIP1) possesses anti-inflammatory activity, and its overexpression reduces liver injury in septic mice. In addition, mice with liver-specific deletion of Zc3h12a develop features of primary biliary cholangitis. In this study, we investigated the role of MCPIP1 in liver fibrosis and HSC activation. METHODS: We analyzed MCPIP1 levels in patients' fibrotic livers and hepatic cells isolated from fibrotic murine livers. In vitro experiments were conducted on primary HSCs, cholangiocytes, hepatocytes, and LX-2 cells with MCPIP1 overexpression or silencing. RESULTS: MCPIP1 levels are induced in patients' fibrotic livers compared with their nonfibrotic counterparts. Murine models of fibrosis revealed that its level is increased in HSCs and hepatocytes. Moreover, hepatocytes with Mcpip1 deletion trigger HSC activation via the release of connective tissue growth factor. Overexpression of MCPIP1 in LX-2 cells inhibits their activation through the regulation of TGFB1 expression, and this phenotype is reversed upon MCPIP1 silencing. CONCLUSIONS: We demonstrated that MCPIP1 is induced in human fibrotic livers and regulates the activation of HSCs in both autocrine and paracrine manners. Our results indicate that MCPIP1 could have a potential role in the development of liver fibrosis.
Asunto(s)
Comunicación Autocrina , Células Estrelladas Hepáticas , Cirrosis Hepática , Comunicación Paracrina , Ribonucleasas , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Animales , Humanos , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Ratones , Ribonucleasas/metabolismo , Ribonucleasas/genética , Masculino , Modelos Animales de Enfermedad , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Hepatocitos/metabolismo , Hepatocitos/patología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Hígado/patología , Hígado/metabolismoRESUMEN
Monocyte-chemoattractant protein-induced protein 1 (MCPIP1, or Regnase-1) is an endoribonuclease that degrades translationally active mRNA molecules. MCPIP1 is mostly known for its anti-inflammatory actions, but it is also an important regulator of adipogenesis and lipid metabolism. Its overexpression impairs adipogenesis by reducing mRNA levels of C/EBPß and PPARγ, key transcription factors regulating this process. Although adipocytes overexpressing MCPIP1 are characterised by impaired glucose uptake, the function of MCPIP1 in hepatocyte metabolism remains unknown. In this study, conditional deletion of Zc3h12a in murine liver epithelial cells was used to characterise the role of Mcpip1 in adaptation to 24-hour food restriction. We found that Mcpip1 deficiency in liver epithelial cells (Mcpip1fl/flAlbCre mice) resulted in higher blood glucose levels in response to fasting in comparison to Mcpip1fl/fl counterparts. Hepatic proteome analysis showed 26 down-regulated and 117 up-regulated proteins in Mcpip1fl/flAlbCre animals that were involved in cellular adhesion, extracellular matrix and metabolic processes. In conclusion, our studies provide new insight into the hepatic function of Mcpip1 and its involvement in metabolic control.
Asunto(s)
Metabolismo de los Lípidos , Hígado , Animales , Ratones , Hepatocitos/metabolismo , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Ribonucleasas/genética , ARN Mensajero/genéticaRESUMEN
Murine models of human diseases are of outmost importance for both studying molecular mechanisms driving their development and testing new treatment strategies. In this review, we first discuss the etiology and risk factors for autoimmune liver disease, including primary biliary cholangitis, autoimmune hepatitis and primary sclerosing cholangitis. Second, we highlight important features of murine transgenic models that make them useful for basic scientists, drug developers and clinical researchers. Next, a brief description of each disease is followed by the characterization of selected animal models.
Asunto(s)
Enfermedades Autoinmunes , Hepatitis Autoinmune , Hepatopatías , Animales , Enfermedades Autoinmunes/genética , Modelos Animales de Enfermedad , Hepatitis Autoinmune/genética , Humanos , Hepatopatías/genética , Ratones , Factores de RiesgoRESUMEN
AIM: The right of underaged patients to confidential health care should be considered an inalienable human right. Access to such care is also advisable according to contemporary medical knowledge. The aim of this study was to verify the extent this right is exercised in Poland and to examine social attitudes towards this issue. METHODS: A sample of Polish school-age pupils and parents (n = 800) was surveyed using an online questionnaire. RESULTS: Only 4.2% of the surveyed adolescents were offered private time with a doctor during their last preventive visit (well-child visit), and this was more frequent for girls. At the same time, a very high level of acceptance for private time with a doctor was observed among Polish adolescents (90.8%) and their parents (84.3%). CONCLUSION: Our findings suggest serious deficiencies in the protection of adolescent patients confidentiality. It is necessary to change medical practice and adapt legal regulations to the provisions of the Convention on the Rights of the Child.