Molecular mechanism underlying impaired hepatic autophagy in glycogen storage disease type Ib. Issue 2 (12th August 2022)

• Record Type: Journal Article
• Authors: Gautam, Sudeep; Zhang, Lisa; Lee, Cheol; Arnaoutova, Irina; Chen, Hung Dar; Resaz, Roberta; Eva, Alessandra; Mansfield, Brian C; Chou, Janice Y
• Is Part Of: Human molecular genetics. Volume 32:Issue 2(2023)
• Page Start: 262
• Page End: 275
• Publication Date: 2022-08-12
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddac197
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Type Ib glycogen storage disease (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that translocates G6P from the cytoplasm into the endoplasmic reticulum lumen, where the intraluminal G6P is hydrolyzed to glucose by glucose-6-phosphatase-α (G6Pase-α). Clinically, GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and a long-term risk of hepatocellular adenoma/carcinoma (HCA/HCC). Studies have shown that autophagy deficiency contributes to hepatocarcinogenesis. In this study, we show that G6PT deficiency leads to impaired hepatic autophagy evident from attenuated expression of many components of the autophagy network, decreased autophagosome formation and reduced autophagy flux. The G6PT-deficient liver displayed impaired sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) signaling, along with reduced expression of SIRT1, forkhead boxO3a (FoxO3a), liver kinase B-1 (LKB1) and the active p-AMPK. Importantly, we show that overexpression of either SIRT1 or LKB1 in G6PT-deficient liver restored autophagy and SIRT1/FoxO3a and LKB1/AMPK signaling. The hepatosteatosis in G6PT-deficient liver decreased SIRT1 expression. LKB1 overexpression reduced hepatic triglyceride levels, providing a potential link between LKB1/AMPK signaling upregulation and the increase in SIRT1 expression. In conclusion, downregulation of SIRT1/FoxO3a and LKB1/AMPK signaling underlies impaired hepatic autophagy which may contribute to HCA/HCC development in GSD-Ib. Understanding this mechanism may guide future therapies. Graphical Abstract: