Pluto Biosciences, Inc

GSE156849: Dissecting the Balance between Metabolic and Oncogenic Functions of Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH)

Bulk RNA sequencing

Obesity is an enormous global health problem and obesity-induced non-alcoholic steatohepatitis (NASH) is contributing to a rising incidence and mortality for hepatocellular carcinoma (HCC). Increase in de novo lipogenesis (DNL) and decrease in fatty acid -oxidation (FAO) underlie hepatic lipid accumulation in NASH. Astrocyte elevated gene-1/metadherin (AEG-1/MTDH) overexpression contributes to both NASH and HCC. AEG-1 harbors an LXXLL motif through which it blocks activation of peroxisome proliferator activated receptor (PPAR), a key regulator of FAO. To better understand the role of LXXLL motif in mediating AEG-1 function, using CRISPR/Cas9 technology, we have generated a novel mouse model (AEG-1-L24K/L25H) in which the LXXLL motif in AEG-1 was mutated to LXXKH. We observed increased activation of PPAR in AEG-1-L24K/L25H livers providing partial protection from high fat diet (HFD)-induced steatosis. Interestingly, even with equal gene dosage levels, compared to AEG-1-WT livers, AEG-1-L24K/L25H livers exhibited increase in levels of lipogenic enzymes, mitogenic activity and inflammation which are attributes observed when AEG-1 is overexpressed. These findings indicate that while LXXLL motif favors steatotic activity of AEG-1 it keeps in check inflammatory and oncogenic functions thus maintaining a homeostasis in AEG-1 function. Conclusion: AEG-1 is being increasingly appreciated as a viable target for ameliorating NASH and NASH-HCC and as such in-depth understanding of the functions and molecular attributes of this molecule is essential. The present studies unravel the unique role of the LXXLL motif in mediating the balance between the metabolic and oncogenic functions of AEG-1. SOURCE: Mikhail Dozmorov (mdozmorov@vcu.edu) - Virginia Commonwealth University

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