Generation of gp78 null mice

Case ID:

Generation of gp78 null mice

WSU Tech#:  15-1291


Generation of the first preclinical experimental model system for gp78-/- C57BL/6 mice, which spontaneously develops age-related nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), linking endoplasmic reticulum-associated degradation (ERAD) to hepatosteatosis, cirrhosis, and cancer. It suggests that gp78 is a regulator of normal liver homeostasis and a tumor suppressor in human liver.

Technology Summary:

gp78 was at first identified as a receptor of autocrine motility factor (AMFR) and was subsequently characterized as a RING-dependent and ER membrane-anchored E3 ligase whose catalytic domains reside in the cytoplasm. It also possesses multiple membrane spanning domains, involved in ubiquitination-mediated degradation of various substrates, including CD3-δ, ApoB lipoprotein, cystic fibrosis transmembrane conductance regulator (CFTR), and the metastasis suppressor KAI1. Others have reported that gp78 might ubiquitinate certain folded proteins and may function as a metabolic regulator of genes such as HMG-CoA reductase (HMGCR) and Insigs involved in lipid metabolism.  Genetic disruption of gp78 in mice developed fatty liver, inflammation and spontaneous hepatocellular cancer in aged mice.


Aging is arguably the most universal risk factor for most of the common diseases, including type 2 diabetes mellitus (T2DM), neurodegeneration and cancer which are frequently associated with metabolic dysregulation and/or accumulation of misfolded protein aggregates.  Visceral adiposity is associated with lipid dysregulation, insulin resistance, and Non-Alcoholic Fatty Liver Disease (NAFLD).  In addition, the liver is the organ responsible for de novo lipogenesis and systemically controls acquisition and removal of triacylglycerol (TG), derived from three sources (diet, de novo synthesis and adipose tissue).  According to previous studies in cultured cells with exogenous cholesterol, gp78 ubiquitinates HMGCR, which is a rate-limiting step in cholesterol biosynthesis and also Insig-2, which inhibits activation of SREBPs (SREBP-1a, -1c), promoting transcription of genes relative to lipid biosynthesis and mobilization.  In agreement with a report of other gp78-KO embryonic fibroblast cells, gp78-KO mice also show no evidence that gp78 is directly implicated in cholesterol synthesis through HMGCR degradation.  Intriguingly, we observed lipid droplets of hepatocytes along with inflammatory infiltration solely at localized regions of liver lobes and not entire regions.  Hepatitis of gp78-KO mice is likely to be independent of steatohepatitis progression.  Results demonstrate that gp78 plays a suppressing role in abnormal fat accumulation and its depletion leads to nonalcoholic steatohepatitis (NASH) in aged mice.


NAFLD, especially the aggressive stage of nonalcoholic steatohepatitis (NASH) is associated with an increased risk of liver cancer and retrospective data suggest that about 27% of cases of NASH transform to HCC after the development of cirrhosis, a late stage of scarring (fibrosis). Interestingly, we observed that overall, >20% (6/25 mice) of the gp78-KO mice developed liver tumors, whereas all WT mice examined were cancer free in the time line examined.  We found that gp78 expression of HCC was significantly lower than that of normal liver tissues (Fig. 4E). The analysis in human HCC specimens suggests etiological linking gp78 loss to HCC and putative tumor suppression although the exact molecular mechanisms underlying progression of NASH to cancer are yet to be determined in gp78-KO mice.


Competitive Advantages


This is a transgenic model system for the progression of age related NASH to HCC.  This is the only known model to accurately demonstrate the characteristics of this transition.  This model is useful in testing therapeutics to treat the process leading up to HCC and/or treating naturally derived HCC in mice.


Stage of Development: Market


Publication Link:  


Patent Status:


No patent filed.


Patent Information:
For Information, Contact:
Nicole Grynaviski
Commercialization Principal
Wayne State University
Avraham Raz
Andrei Golovko