A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis

被引:6
作者
Arends, Charles J. [1 ,2 ]
Wilson, Lane H. [1 ,3 ]
Estrella, Ana [1 ]
Kwon, Oh Sung [4 ,5 ]
Weinstein, David A. [1 ]
Lee, Young Mok [1 ,2 ]
机构
[1] Univ Connecticut, Sch Med, Dept Pediat, Farmington, CT 06030 USA
[2] Univ Connecticut, Dept Genet & Genome Sci, Hlth Ctr, Farmington, CT 06030 USA
[3] Univ Penn, Perelman Sch Med, Dept Med, Gene Therapy Program, Philadelphia, PA 19104 USA
[4] Univ Connecticut, Dept Kinesiol, Storrs, CT 06269 USA
[5] Univ Connecticut, Ctr Aging, Dept Orthpaed Surg, Hlth Ctr, Farmington, CT 06030 USA
关键词
glycogenolysis; hepatomegaly; hypoglycemia; ketosis; glucose; PHOSPHORYLASE-KINASE DEFICIENCY; LIVER GLYCOGENOSIS; NATURAL-HISTORY; MUTATIONS; VARIABILITY; ISOFORM; MUSCLE; RAT;
D O I
10.3390/ijms23179944
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (alpha, beta, gamma, delta). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the alpha -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb(-/-)) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb(-/-) mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb(-/-) mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb(-/-) mice. Gene expression analysis and liver histology in the livers of old Phkb(-/-) mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb(-/-) mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb(-/-) mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.
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页数:12
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