Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 10, Pages 1890-1899Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx097
Keywords
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Funding
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institutes of Health
- Children's Fund for Glycogen Storage Disease Research
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Glycogen storage disease type Ia (GSD- Ia) is characterized by impaired glucose homeostasis and long-termrisks of hepatocellular adenoma (HCA) and carcinoma (HCC). We have shown that the non-tumor-bearing (NT), recombinant adeno-associated virus (rAAV) vector-treated GSD-Ia mice (AAV-NT mice) expressing a wide range (0.9-63%) of normal hepatic glucose-6-phosphatase-alpha activity maintain glucose homeostasis and display physiologic features mimicking animals living under calorie restriction (CR). We now show that in AAV-NT mice, the signaling pathways of the CR mediators, AMP-activated protein kinase (AMPK) and sirtuin-1 are activated. AMPK/sirtuin-1 inhibit the activity of STAT3 (signal transducer and activator of transcription 3) and NF kappa B (nuclear factor kappa B), the pro-inflammatory and cancer-promoting transcription factors. Sirtuin-1 also inhibits cancer metastasis via increasing the expression of E-cadherin, a tumor suppressor, and decreasing the expression of mesenchymal markers. Consistently, in AAV-NT mice, hepatic levels of active STAT3 and NF kappa B-p65 were reduced as were expression of mesenchymal markers, STAT3 targets, NF kappa B targets and beta-catenin targets, all of which were consistent with the promotion of tumorigenesis. AAV-NT mice also expressed increased levels of E-cadherin and fibroblast growth factor 21 (FGF21), targets of sirtuin-1, and beta-klotho, which can acts as a tumor suppressor. Importantly, treating AAV-NT mice with a sirtuin-1 inhibitor markedly reversed many of the observed anti-inflammatory/anti-tumorigenic signaling pathways. In summary, activation of hepatic AMPK/sirtuin-1 and FGF21/beta-klotho signaling pathways combined with down-regulation of STAT3/NF kappa B-mediated inflammatory and tumorigenic signaling pathways can explain the absence of hepatic tumors in AAV-NT mice.
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