Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer.
Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinyl...
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doaj-f5eb3982a79b4fcda3532c91502035552020-11-24T21:30:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e011844810.1371/journal.pone.0118448Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer.Tianpeng ZhangDhong Hyo KhoYing WangYosuke HarazonoKosei NakajimaYouming XieAvraham RazNonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH. Liver histology of gp78-/- mice revealed typical steatosis, hepatic inflammation and fibrosis, followed by progression to hepatocellular tumors. Acute ER stress revealed that loss of gp78 results in up regulation of unfolded protein response (UPR) pathways and SREBP-1 regulating de novo lipogenesis, responsible for fatty liver. Tissue array of human hepatocellular carcinoma (HCC) demonstrated that the expression of gp78 was inversely correlated with clinical grades of cancer. Here, we have described the generation of the first preclinical experimental model system which spontaneously develops age-related NASH and HCC, linking ERAD to hepatosteatosis, cirrhosis, and cancer. It suggests that gp78 is a regulator of normal liver homeostasis and a tumor suppressor in human liver.http://europepmc.org/articles/PMC4366401?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tianpeng Zhang Dhong Hyo Kho Ying Wang Yosuke Harazono Kosei Nakajima Youming Xie Avraham Raz |
spellingShingle |
Tianpeng Zhang Dhong Hyo Kho Ying Wang Yosuke Harazono Kosei Nakajima Youming Xie Avraham Raz Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. PLoS ONE |
author_facet |
Tianpeng Zhang Dhong Hyo Kho Ying Wang Yosuke Harazono Kosei Nakajima Youming Xie Avraham Raz |
author_sort |
Tianpeng Zhang |
title |
Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. |
title_short |
Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. |
title_full |
Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. |
title_fullStr |
Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. |
title_full_unstemmed |
Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. |
title_sort |
gp78, an e3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (nash) and liver cancer. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH. Liver histology of gp78-/- mice revealed typical steatosis, hepatic inflammation and fibrosis, followed by progression to hepatocellular tumors. Acute ER stress revealed that loss of gp78 results in up regulation of unfolded protein response (UPR) pathways and SREBP-1 regulating de novo lipogenesis, responsible for fatty liver. Tissue array of human hepatocellular carcinoma (HCC) demonstrated that the expression of gp78 was inversely correlated with clinical grades of cancer. Here, we have described the generation of the first preclinical experimental model system which spontaneously develops age-related NASH and HCC, linking ERAD to hepatosteatosis, cirrhosis, and cancer. It suggests that gp78 is a regulator of normal liver homeostasis and a tumor suppressor in human liver. |
url |
http://europepmc.org/articles/PMC4366401?pdf=render |
work_keys_str_mv |
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