Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency

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• 作者：Benjamin L. Farah¹ ; Dustin J. Landau² ; Rohit A. Sinha¹ ; Elizabeth D. Brooks² ; ³ ; Yajun Wu⁴ ; Suet Yin Sarah Fung⁵ ; Tomohiro Tanaka⁶ ; Masahiro Hirayama⁶ ; Boon-Huat Bay⁴ ; Dwight D. Koeberl² ; ⁷ ; ^{dwight.koeberl@duke.edu" class="auth_mail" title="E-mail the corresponding author} ; Paul M. Yen¹ ; ⁸ ; ^{paul.yen@duke-nus.edu.sg" class="auth_mail" title="E-mail the corresponding author}
• 关键词：G6Pase α ; glucose-6-phosphatase α ; G6PC ; glucose-6-phosphatase α catalytic subunit ; GSDIa ; glycogen storage disease type Ia ; G6P ; glucose-6-phosphate ; mTOR ; mammalian target of rapamycin ; AMPK ; 5&rsquo ; AMP-activated protein kinase ; ULK1 ; Unc51-like kinase 1 ; NAFLD ; non-alcoholic fatty liver disease ; GSDII ; glycogen storage disease type II ; LC3 ; microtubule-associated protein 1A/1B-light chain 3 ; C-C3 ; cleaved caspase 3 ; Rap ; rapamycin ; AAV ; adeno-associated virus ; GFP ; green fluorescent protein
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：370-379
• 全文大小：3663 K

文摘

Glucose-6-phosphatase (G6Pase α, G6PC) deficiency, also known as von Gierke’s disease or GSDIa, is the most common glycogen storage disorder. It is characterized by a decreased ability of the liver to convert glucose-6-phosphate (G6P) to glucose leading to glycogen and lipid over-accumulation progressing to liver failure and/or hepatomas and carcinomas. Autophagy of intracellular lipid stores (lipophagy) has been shown to stimulate fatty acid β-oxidation in hepatic cells. Thus, we examined autophagy and its effects on reducing hepatic lipid over-accumulation in several cell culture and animal models of GSDIa.

Methods

Autophagy in G6PC-deficient hepatic cell lines, mice, and dogs was measured by Western blotting for key autophagy markers. Pro-autophagic Unc51-like kinase 1 (ULK1/ATG1) was overexpressed in G6PC-deficient hepatic cells, and lipid clearance and oxidative phosphorylation measured. G6PC^−/− mice and GSDIa dogs were treated with rapamycin and assessed for liver function.

Results

Autophagy was impaired in the cell culture, mouse, and canine models of GSDIa. Stimulation of the anti-autophagic mTOR, and inhibition of the pro-autophagic AMPK pathways occurred both in vitro and in vivo. Induction of autophagy by ULK1/ATG1 overexpression decreased lipid accumulation and increased oxidative phosphorylation in G6PC-deficient hepatic cells. Rapamycin treatment induced autophagy and decreased hepatic triglyceride and glycogen content in G6PC^−/− mice, as well as reduced liver size and improved circulating markers of liver damage in GSDIa dogs.

Conclusions

Autophagy is impaired in GSDIa. Pharmacological induction of autophagy corrects hepatic lipid over-accumulation and may represent a new therapeutic strategy for GSDIa.