title: Ketogenic essential amino acids replacement diet ameliorated hepatosteatosis with altering autophagy-associated molecules.
abstract: 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 (HFD(KAAR)) 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. HFD(KAAR) 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.
authors.affiliation: Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Megumi
authors.initials: M
authors.lastname: Kanasaki
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagao
authors.forename: Hiroko
authors.initials: H
authors.lastname: Jinzu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000601:Amino Acids, Essential / Q000008:administration & dosage*; D000818:Animals; D001343:Autophagy; D001835:Body Weight; D055423:Diet, Ketogenic; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000178:diet therapy*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size
chemical_list: D000601:Amino Acids, Essential; D004041:Dietary Fats
keywords: AMPK; Amino acid; Atg; Autophagy; Fatty liver; Foxo; HFD; KAA; LC-3; LKB1; Metabolic syndrome; Nutritional intervention; Obesity; adenine monophosphate-activated protein kinase; autophagy-related protein; forkhead homeobox type O; high fat diet; ketogenic amino acids; light chain-3; liver kinase B1; mTOR; mammalian target of rapamycin