Female GADD34 mice develop age-related inflammation and hepatocellular carcinoma

Geriatr Gerontol Int. 2017 Dec;17(12):2593-2601. doi: 10.1111/ggi.13080. Epub 2017 Jun 21.

Abstract

Aim: To analyze the impact of sex on GADD34 function, we studied the aging of female GADD34-deficient mice and compared them with male GADD34-deficient mice.

Methods: We used GADD34-deficient mice on a C57BL/6 background. These mice were fed a normal diet throughout their life. Alternatively, they were fed a high-fat diet at 3 months-of-age. Liver tissues taken from mice were analyzed by hematoxylin-eosin staining and immunohistochemical methods. Fresh liver cells were analyzed by flow cytometry.

Results: We found that female GADD34-deficient mice did not develop obesity or fatty livers. However, female GADD34-deficient mice had infiltrations of myeloid cells in the liver, followed by liver atrophy. Many female GADD34-deficient mice developed hepatocellular carcinoma, whereas female wild-type (WT) mice did not show hepatocellular carcinoma during aging. Female GADD34-deficient mice and female WT mice developed the same percentages of lymphoma. Although a high-fat diet induced a higher level of steatosis in young male GADD34-deficient mice compared with WT mice, a high-fat diet induced the same level of steatosis in young female GADD34-deficient mice compared with WT mice. However, GADD34-deficient female young mice had a higher level of infiltration of myeloid cells and myofibroblasts than WT mice.

Conclusions: In contrast to male GADD34-deficient mice, female GADD34-deficient mice did not show obesity as they aged. However, similar to the males, they developed inflammation followed by hepatocellular carcinoma. Geriatr Gerontol Int 2017; 17: 2593-2601.

Keywords: GADD34; biomedical gerontology; gender; hepatocellular carcinoma; inflammation.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / etiology*
  • Fatty Liver
  • Female
  • Inflammation / etiology
  • Liver
  • Liver Diseases / etiology*
  • Liver Neoplasms
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells
  • Neutrophil Infiltration
  • Obesity / etiology
  • Protein Phosphatase 1*
  • Sex Factors*

Substances

  • Ppp1r15a protein, mouse
  • Protein Phosphatase 1