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.

3">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.