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

Nishio N, Isobe K - Sci Rep (2015)

Bottom Line: 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.Differentiation into fat is dependent on insulin signaling.We found that a HFD or palmitate treatment converted insulin signaling by up-regulating TNF-α and JNK.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550.

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.

No MeSH data available.


Related in: MedlinePlus

GADD34 -deficient mice accumulated a fat in liver with aging.(a) Sections of the liver of 15 M old male WT (upper) and GADD34 -deficient (lower) mice were stained with H&E, Masson’s trichrome and Oil Red O. (b) Bone marrow cells were stained with anti-CD24, Sca-1 and CD34 antibodies. Graph (right) shows CD24+/Sca-1+/CD34+ adipocyte progenitor cells in bone marrow. Representative results of three independent experiments are shown. Data shown are the mean ratio ± SEM. (*p < 0.05).
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f2: GADD34 -deficient mice accumulated a fat in liver with aging.(a) Sections of the liver of 15 M old male WT (upper) and GADD34 -deficient (lower) mice were stained with H&E, Masson’s trichrome and Oil Red O. (b) Bone marrow cells were stained with anti-CD24, Sca-1 and CD34 antibodies. Graph (right) shows CD24+/Sca-1+/CD34+ adipocyte progenitor cells in bone marrow. Representative results of three independent experiments are shown. Data shown are the mean ratio ± SEM. (*p < 0.05).

Mentions: We examined whether GADD34-deficient mice fed ND developed nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) with age. Using hematoxylin and eosin (H&E) and Oil Red O staining, we observed higher fat levels in the liver cells of GADD34-deficient mice than in those of WT mice (Fig. 2a). Because bone marrow progenitor (BMP)–derived adipocytes had been shown to accumulate preferentially in visceral fat depots and GADD34-deficient mice showed higher levels of fat droplets and adipocytes than did WT mice with age21, we compared these adipocytes between GADD34-deficient and WT mouse bone marrow. GADD34-deficient bone marrow at 4 and 12 months showed higher numbers of CD24+/Sca1+/CD34+ cells than those of WT mice (Fig. 2b).


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

Nishio N, Isobe K - Sci Rep (2015)

GADD34 -deficient mice accumulated a fat in liver with aging.(a) Sections of the liver of 15 M old male WT (upper) and GADD34 -deficient (lower) mice were stained with H&E, Masson’s trichrome and Oil Red O. (b) Bone marrow cells were stained with anti-CD24, Sca-1 and CD34 antibodies. Graph (right) shows CD24+/Sca-1+/CD34+ adipocyte progenitor cells in bone marrow. Representative results of three independent experiments are shown. Data shown are the mean ratio ± SEM. (*p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4551985&req=5

f2: GADD34 -deficient mice accumulated a fat in liver with aging.(a) Sections of the liver of 15 M old male WT (upper) and GADD34 -deficient (lower) mice were stained with H&E, Masson’s trichrome and Oil Red O. (b) Bone marrow cells were stained with anti-CD24, Sca-1 and CD34 antibodies. Graph (right) shows CD24+/Sca-1+/CD34+ adipocyte progenitor cells in bone marrow. Representative results of three independent experiments are shown. Data shown are the mean ratio ± SEM. (*p < 0.05).
Mentions: We examined whether GADD34-deficient mice fed ND developed nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) with age. Using hematoxylin and eosin (H&E) and Oil Red O staining, we observed higher fat levels in the liver cells of GADD34-deficient mice than in those of WT mice (Fig. 2a). Because bone marrow progenitor (BMP)–derived adipocytes had been shown to accumulate preferentially in visceral fat depots and GADD34-deficient mice showed higher levels of fat droplets and adipocytes than did WT mice with age21, we compared these adipocytes between GADD34-deficient and WT mouse bone marrow. GADD34-deficient bone marrow at 4 and 12 months showed higher numbers of CD24+/Sca1+/CD34+ cells than those of WT mice (Fig. 2b).

Bottom Line: 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.Differentiation into fat is dependent on insulin signaling.We found that a HFD or palmitate treatment converted insulin signaling by up-regulating TNF-α and JNK.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550.

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.

No MeSH data available.


Related in: MedlinePlus