title: GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance.
abstract: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in parallel with the prevalence of obesity. DNA damage-inducible protein 34 (GADD34/Ppp1r15a), originally isolated from UV-inducible transcripts in Chinese hamster ovary (CHO) cells, dephosphorylates several kinases that function in important signaling cascades, including dephosphorylation of eIF2α. We examined the effects of GADD34 on natural life span by using GADD34-deficient mice. Here we observed for the first time that with age GADD34-deficient mice become obese, developing fatty liver followed by liver cirrhosis, hepatocellular carcinoma, and insulin resistance. We found that myofibroblasts and immune cells infiltrated the portal veins of aged GADD34-deficient mouse livers. A high-fat diet (HFD) induced a higher level of steatosis in young GADD34-deficient mice compared with WT mice. Differentiation into fat is dependent on insulin signaling. Insulin signaling in young GADD34-deficient mice was higher than that in WT mice, which explained the higher fat differentiation of mouse embryonic fibroblasts (MEFs) observed in GADD34-deficient mice. Through aging or a HFD, insulin signaling in GADD34-deficient liver converted to be down regulated compared with WT mice. We found that a HFD or palmitate treatment converted insulin signaling by up-regulating TNF-α and JNK.
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550.
authors: Naomi
authors: N
authors: Nishio
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550.|Department of Food Science and Nutrition, Nagoya woman's university, 3-40 Shioji-cho, Mizuho-ku, Nagoya, Aichi, 467-0003 Japan.
authors: Ken-ichi
authors: K
authors: Isobe
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000375:Aging / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000150:complications / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000150:complications* / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000473:pathology; D009765:Obesity / Q000150:complications* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D019308:Palmitic Acid; D048031:JNK Mitogen-Activated Protein Kinases; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1