Generation of a glycogen storage disease mouse model with fatty liver and its treatment by PPAR-α agonist bezafibrate

Abstract

Background Fatty liver is considered the pathological basis for the development of glycogen storage disease type Ia (GSDIa); however, due to the lack of suitable animal models, the mechanism underlying fatty liver development in GSDIa is largely unknown. Methods This study employed surrogate breastfeeding to enable the survival of glucose-6-phosphatase catalytic (G6PC) knockout (KO) mice into adulthood, and then analyzed fatty liver phenotypes in 3-month-old KO (KO-3), 6-month-old KO (KO-6), and 9-month-old KO (KO-9) mice. Results KO-6 and KO-9 mice exhibited typical fatty liver phenotypes, and upregulation of glucose-6-phosphate (G6P). Moreover, both Western blot and qRT-PCR analysis showed significant upregulation of ChREBP, SREBP1 and fatty acid synthesis enzymes. RNA-seq heat maps revealed that KO-6 and KO-9 mice exhibited similar expression patterns, distinct from those observed in the wild-type (WT) and KO-3 groups. GO and KEGG analysis further revealed changes in lipid metabolism pathways in KO-6 and KO-9 mice, as well as PI3K-Akt, AMPK, and MAPK signaling. Western blot analysis showed that the Akt and mTOR pathways were activated, while the AMPK pathway was downregulated, indicating impaired autophagy. Finally, bezafibrate, a proliferator-activated receptor α (PPAR-α) agonist, enhanced autophagic activity and attenuated inflammatory responses, fat deposition, and glycogen storage in G6PC KO mice. Conclusion This study successfully generated a fatty liver model using G6PC KO adult mice and demonstrated that pharmacological activation of PPAR-α may have therapeutic potential in adult G6PC KO mice.