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Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C.
J Hepatol. 2011 Jan; 54(1):142-52.JH

Abstract

BACKGROUND & AIMS

We aimed to elucidate whether hepatic insulin resistance may contribute to hepatocyte apoptosis and fibrogenesis in nonalcoholic fatty liver disease (NAFLD) and in chronic hepatitis C virus (HCV) infection.

METHODS

Twenty-seven nonalcoholic steatosis (NAST), 24 nonalcoholic steatohepatitis (NASH), 71 HCV, and 29 patients with histological normal liver (NL) were studied. Real-time PCR, the TUNEL assay, and Western blots were used to assess insulin-signaling molecules, hepatocyte apoptosis, antiapoptotic mediators, active caspase 3, and type I collagen in liver biopsies. HCV core-transfected human hepatocytes were used as an in vitro model.

RESULTS

In NAFLD patients, hepatic levels of insulin receptor substrate (IRS) 1, IRS2 2, the p85α subunit of phosphatidylinositol 3-kinase (p85α), phosphorylated protein kinase B (pAkt), phosphorylated forkhead box-containing protein O subfamily-1 (FoxO), and phosphorylated 5' adenosine monophosphate-activated protein kinase (pAMPK) as well as the antiapoptotic mediators B-cell lymphoma 2 protein (Bcl-2) and myeloid cell leukemia protein-1 (Mcl-1) were significantly lower in NASH than in NAST and NL. Furthermore, hepatocyte apoptosis and increased active caspase 3 were only present in NASH. In HCV patients, hepatic insulin signaling was markedly impaired, regardless of viral genotype and the presence of steatosis paralleled with enhanced apoptosis. In cultured human hepatocytes, HCV core protein decreased pAkt and increased phosphorylation of c-Jun N-terminal kinase (JNK). This effect was more pronounced in lipid-loaded hepatocytes.

CONCLUSIONS

Hepatic insulin signaling is impaired in NASH and HCV patients, and downregulation of insulin-sensitive targets is associated with increased apoptosis and fibrogenesis in both conditions. JNK might be a target for HCV-induced insulin resistance.

Authors+Show Affiliations

Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20888662

Citation

García-Monzón, Carmelo, et al. "Hepatic Insulin Resistance Is Associated With Increased Apoptosis and Fibrogenesis in Nonalcoholic Steatohepatitis and Chronic Hepatitis C." Journal of Hepatology, vol. 54, no. 1, 2011, pp. 142-52.
García-Monzón C, Lo Iacono O, Mayoral R, et al. Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C. J Hepatol. 2011;54(1):142-52.
García-Monzón, C., Lo Iacono, O., Mayoral, R., González-Rodríguez, A., Miquilena-Colina, M. E., Lozano-Rodríguez, T., García-Pozo, L., Vargas-Castrillón, J., Casado, M., Boscá, L., Valverde, A. M., & Martín-Sanz, P. (2011). Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C. Journal of Hepatology, 54(1), 142-52. https://doi.org/10.1016/j.jhep.2010.06.021
García-Monzón C, et al. Hepatic Insulin Resistance Is Associated With Increased Apoptosis and Fibrogenesis in Nonalcoholic Steatohepatitis and Chronic Hepatitis C. J Hepatol. 2011;54(1):142-52. PubMed PMID: 20888662.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C. AU - García-Monzón,Carmelo, AU - Lo Iacono,Oreste, AU - Mayoral,Rafael, AU - González-Rodríguez,Agueda, AU - Miquilena-Colina,María E, AU - Lozano-Rodríguez,Tamara, AU - García-Pozo,Leonor, AU - Vargas-Castrillón,Javier, AU - Casado,Marta, AU - Boscá,Lisardo, AU - Valverde,Angela M, AU - Martín-Sanz,Paloma, Y1 - 2010/08/27/ PY - 2010/01/19/received PY - 2010/05/06/revised PY - 2010/06/08/accepted PY - 2010/10/5/entrez PY - 2010/10/5/pubmed PY - 2011/3/25/medline SP - 142 EP - 52 JF - Journal of hepatology JO - J. Hepatol. VL - 54 IS - 1 N2 - BACKGROUND & AIMS: We aimed to elucidate whether hepatic insulin resistance may contribute to hepatocyte apoptosis and fibrogenesis in nonalcoholic fatty liver disease (NAFLD) and in chronic hepatitis C virus (HCV) infection. METHODS: Twenty-seven nonalcoholic steatosis (NAST), 24 nonalcoholic steatohepatitis (NASH), 71 HCV, and 29 patients with histological normal liver (NL) were studied. Real-time PCR, the TUNEL assay, and Western blots were used to assess insulin-signaling molecules, hepatocyte apoptosis, antiapoptotic mediators, active caspase 3, and type I collagen in liver biopsies. HCV core-transfected human hepatocytes were used as an in vitro model. RESULTS: In NAFLD patients, hepatic levels of insulin receptor substrate (IRS) 1, IRS2 2, the p85α subunit of phosphatidylinositol 3-kinase (p85α), phosphorylated protein kinase B (pAkt), phosphorylated forkhead box-containing protein O subfamily-1 (FoxO), and phosphorylated 5' adenosine monophosphate-activated protein kinase (pAMPK) as well as the antiapoptotic mediators B-cell lymphoma 2 protein (Bcl-2) and myeloid cell leukemia protein-1 (Mcl-1) were significantly lower in NASH than in NAST and NL. Furthermore, hepatocyte apoptosis and increased active caspase 3 were only present in NASH. In HCV patients, hepatic insulin signaling was markedly impaired, regardless of viral genotype and the presence of steatosis paralleled with enhanced apoptosis. In cultured human hepatocytes, HCV core protein decreased pAkt and increased phosphorylation of c-Jun N-terminal kinase (JNK). This effect was more pronounced in lipid-loaded hepatocytes. CONCLUSIONS: Hepatic insulin signaling is impaired in NASH and HCV patients, and downregulation of insulin-sensitive targets is associated with increased apoptosis and fibrogenesis in both conditions. JNK might be a target for HCV-induced insulin resistance. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/20888662/Hepatic_insulin_resistance_is_associated_with_increased_apoptosis_and_fibrogenesis_in_nonalcoholic_steatohepatitis_and_chronic_hepatitis_C_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(10)00711-7 DB - PRIME DP - Unbound Medicine ER -