Molecular mechanism underlying impaired hepatic autophagy in glycogen storage disease type Ib

Abstract

Type Ib glycogen storage disease (GSD-Ib) is caused by a deficiency in the 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 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 triglycerides 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.

Ethanol Extract of Rosa rugosa Ameliorates Acetaminophen-Induced Liver Injury via Upregulating Sirt1 and Subsequent Potentiation of LKB1/AMPK/Nrf2 Cascade in Hepatocytes

“…As a catalytic activity of Sirt1 is enhanced, phosphorylation of LKB1 and AMPK is thereby considerably upregulated [63]. Additionally, overexpression of Sirt1 in the liver activates the hepatic LKB1/AMPK axis and promotes Nrf2-dependent gene transcription [64,65]. Under APAP stimulation, levels of Sirt1 in the liver decline, which can be further supported by our current study [46,66].…”

A novel GK Ala469Val variant resulting in glycerol kinase deficiency with concurrent hepatoblastoma: A case report

“…The pathogenesis of the rare association of hepatoblastoma and hepatocellular carcinoma with GSD and other IEM is not well understood. Previous suggested mechanisms include glucose/insulin imbalance, cellular glycogen imbalance, autophagy impairment, inflammation activation, proto-oncogene activation and activation of multiple tumor-promoting pathways, exposure to toxic metabolites such as argininosuccinic acid and/or arginine, and/or impairment of the glutathione metabolism (the major antioxidant in the liver) [ [17] , [18] , [19] , [20] , [21] , [22] ]. To our knowledge, this is the first report of hepatoblastoma and GKD occurring together.…”

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders

“…Mechanisms of inhibition of autophagy are likely to be involved. Remarkably, impaired autophagy has recently been demonstrated in a mouse model of GSDIb (141). For its proautophagic effect, empagliflozin may represent a good candidate for the treatment of hepatic GSDs.…”