Frontiers in pharmacology · 2026
Generation of a glycogen storage disease mouse model with fatty liver and its treatment by PPAR-α agonist bezafibrate.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Xie Yixia, Fu Guoquan, Fan Caixia, Huang Huarong, Yan Junyan, Jin Lifang
Аннотация
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.
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.