GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance

Scientific Reports
Naomi Nishio, Ken-Ichi Isobe

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 wi...Continue Reading

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Citations

Mar 18, 2017·Nature Communications·Yan ZhangHermann Brenner
Jun 22, 2017·Geriatrics & Gerontology International·Naomi NishioKen-Ichi Isobe
May 30, 2019·Cell Death & Disease·Christopher R Starr, Marina S Gorbatyuk
Jun 9, 2017·American Journal of Respiratory Cell and Molecular Biology·Abdelnaby KhalyfaDavid Gozal
Dec 8, 2020·Frontiers in Cell and Developmental Biology·Xin WenCheng-Guang Liang
Apr 10, 2020·Progress in Retinal and Eye Research·Marina S GorbatyukOleg S Gorbatyuk

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Methods Mentioned

BETA
FACS
ELISA
protein assay
PCR

Software Mentioned

FlowJo
TreeStar

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