Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1832, Issue 10, Pages 1605-1612Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2013.05.003
Keywords
Metabolic syndrome; Obesity; Fatty liver; Amino acid; Nutritional intervention; Autophagy
Funding
- Japan Society for the Promotion of Science [24790329, 24591218, 23790381, 25670414, 25282028]
- Kanazawa Medical University [SR2012-06, C2011-4, C2012-1, S2011-2, S2012-4, S2011-1, S2012-5]
- Uehara Memorial Foundation
- Japan Research Foundation for Clinical Pharmacology
- Daiichi-Sankyo Foundation of Life Science
- Ono Medical Research Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Takeda Science Foundation
- Banyu Foundation
- Grants-in-Aid for Scientific Research [24790329, 24591218, 25670414] Funding Source: KAKEN
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Ketogenic amino acid (KAA) replacement diet has been shown to cure hepatic steatosis, a serious liver disease associated with diverse metabolic defects. In this study, we investigated the effects of KAA replacement diet on nutrition sensing signaling pathway and analyzed whether induction of hepatic autophagy was involved. Mice are fed with high fat diet (HFD) or KAA replacement in high-fat diet (30% fat in food; HFD)-fed (HFDKAAR) and sacrificed at 8, 12, 16 weeks after initiation of experimental food. Hepatic autophagy was analyzed in protein expression of several autophagy-associated molecules and in light chain-3 green fluorescent protein (LC-3 GFP) transgenic mice. HFDKAAR showed increased AMP-activated protein kinase (AMPK) phosphorylation and enhanced liver kinase B1 (LKB1) expression compared to control HFD-fed mice. The KAA-HFD-induced activation of AMPK was associated with an increased protein expression of sirtuin 1 (Sirt1), decreased forkhead box protein O3a (Foxo3a) level, and suppression of mammalian target of rapamycin (mTOR) phosphorylation compared with the HFD-fed mice. The intervention study revealed that a KAA-replacement diet also ameliorated all the established metabolic and autophagy defects in the HFD-fed mice, suggesting that a KAA-replacement diet can be used therapeutically in established diseases. These results indicate that KAA replacement in food could be a novel strategy to combat hepatic steatosis and metabolic abnormalities likely involvement of an induction of autophagy. (C) 2013 Elsevier B.V. All rights reserved.
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