title: Metabolic adaptations to interrupted glycosaminoglycan recycling.
abstract: Lysosomal storage diseases (LSD) are metabolic disorders characterized by accumulation of undegraded material. The mucopolysaccharidoses (MPS) are LSDs defined by the storage of glycosaminoglycans. Previously, we hypothesized that cells affected with LSD have increased energy expenditure for biosynthesis because of deficiencies of raw materials sequestered within the lysosome. Thus, LSDs can be characterized as diseases of deficiency as well as overabundance (lysosomal storage). In this study, metabolite analysis identified deficiencies in simple sugars, nucleotides, and lipids in the livers of MPSI mice. In contrast, most amino acids, amino acid derivatives, dipeptides, and urea were elevated. These data suggest that protein catabolism, perhaps because of increased autophagy, is at least partially fulfilling intermediary metabolism. Thus, maintaining glycosaminoglycan synthesis in the absence of recycled precursors results in major shifts in the energy utilization of the cells. A high fat diet increased simple sugars and some fats and lowered the apparent protein catabolism. Interestingly, autophagy, which is increased in several LSDs, is responsive to dietary intervention and is reduced in MPSVII and MPSI mice fed a high fat diet. Although long term dietary treatment improved body weight in MPSVII mice, it failed to improve life span or retinal function. In addition, the ventricular hypertrophy and proximal aorta dilation observed in MPSVII mice were unchanged by a high fat, simple sugar diet. As the mechanism of this energy imbalance is better understood, a more targeted nutrient approach may yet prove beneficial as an adjunct therapy to traditional approaches.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Josh C
authors.initials: JC
authors.lastname: Woloszynek
authors.forename: Atilla
authors.initials: A
authors.lastname: Kovacs
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ohlemiller
authors.forename: Marie
authors.initials: M
authors.lastname: Roberts
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004040:Dietary Carbohydrates / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D009083:Mucopolysaccharidoses / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D006025:Glycosaminoglycans; C020341:glucosaminoglycans
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