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HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma.
Fekry, Baharan; Ribas-Latre, Aleix; Baumgartner, Corrine; Mohamed, Alaa M T; Kolonin, Mikhail G; Sladek, Frances M; Younes, Mamoun; Eckel-Mahan, Kristin L.
Afiliación
  • Fekry B; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
  • Ribas-Latre A; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
  • Baumgartner C; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
  • Mohamed AMT; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
  • Kolonin MG; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
  • Sladek FM; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
  • Younes M; Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, California.
  • Eckel-Mahan KL; Department of Pathology and Laboratory Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.
Cancer Res ; 79(22): 5860-5873, 2019 11 15.
Article en En | MEDLINE | ID: mdl-31575546
ABSTRACT
The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of nonalcoholic fatty liver disease, which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ("P1-HNF4α") in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the "STAM" model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic HF diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in IL6, a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial-mesenchymal transition in an IL6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC.

SIGNIFICANCE:

This study provides a mechanism for the growing incidence of hepatocellular carcinoma in both men and women, which is linked to nonalcoholic fatty liver disease.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Factor Nuclear 4 del Hepatocito / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Cancer Res Año: 2019 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Factor Nuclear 4 del Hepatocito / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Cancer Res Año: 2019 Tipo del documento: Article