Abstract
Sodium valporate (VPA), a broad-spectrum inhibitor of histone deacetylases (HDACs), increased ghrelin whereas decreased nesfatin-1 in mice fed normal chow diet or high-fat diet. Alterations in ghrelin and nucleobindin 2/nesfatin-1 were mediated by HDAC5 but not HDAC4. Activation of mTORC1 significantly attenuated the effect of VPA on ghrelin and nesfatin-1 levels. HDAC5 coimmunoprecipitated with raptor. Inhibition of HDAC5 by VPA, trichostatin A, or siHDAC5 markedly increased acetylation of raptor Lys840 and subsequent phosphorylation of raptor Ser792, resulting in suppression of mTORC1 signaling. A raptor mutant lacking the Lys840 acetylation site showed a decrement in phosphorylation of raptor Ser792 and subsequent increase in mTORC1 signaling. These alterations were associated with reciprocal changes in ghrelin and nucleobindin 2/nesfatin-1 expression. These findings reveal HDAC5-mTORC1 signaling as a novel mechanism in the differential regulation of gastric ghrelin and nesfatin-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Calcium-Binding Proteins / metabolism*
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Cell Line
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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Gastric Mucosa / metabolism
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Ghrelin / metabolism*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Hydroxamic Acids / pharmacology
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / metabolism*
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Nerve Tissue Proteins / metabolism*
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Nucleobindins
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Obesity / pathology
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Phosphorylation / drug effects
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RNA Interference
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RNA, Small Interfering / genetics
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Regulatory-Associated Protein of mTOR
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism*
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Valproic Acid / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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Calcium-Binding Proteins
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DNA-Binding Proteins
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Ghrelin
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Hydroxamic Acids
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Multiprotein Complexes
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Nerve Tissue Proteins
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Nucb1 protein, mouse
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Nucleobindins
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RNA, Small Interfering
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Regulatory-Associated Protein of mTOR
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Rptor protein, mouse
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trichostatin A
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Valproic Acid
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Hdac5 protein, mouse
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Histone Deacetylases