Metabolite Regulation of Nucleo-cytosolic Trafficking of Carbohydrate Response Element-binding Protein (ChREBP)

Nakagawa, Tsutomu; Ge, Qiang; Pawlosky, Robert J.; Wynn, R. Max; Veech, Richard L.; Uyeda, Kosaku

doi:10.1074/jbc.m113.498550

Cited by 44 publications

(61 citation statements)

References 24 publications

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“…Early investigations of AA utilization in animals using 14 C-labeled AA indicated that most of the AA was recovered as respiratory 14 CO 2 ; however, a small amount of AA was incorporated into proteins (85,86). Intriguingly, while our manuscript was being submitted, T. Nakagawa et al (87) reported their recent work in which they have provided experimental evidence to show that ketone bodies (3HB and AA) could serve as low glucose signaling by regulating nucleo-cytosolic trafficking of ChREBP through promoting interaction of ChREBP/14-3-3 and inhibiting ChREBP/importin interaction. This is the first demonstration that ketone bodies could physically interact with cellular proteins.…”

Section: Discussionmentioning

confidence: 92%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

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Section: Discussionmentioning

confidence: 92%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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“…5C ), a reported modifi cation that results in higher ChREBP nuclear translocation and transcriptional activity ( 37 ). Detailed studies of the posttranslational modifi cation and transcriptional coregulators associated with ChREBP will be necessary to completely understand the actions of leptin on the transcriptional control of hepatic lipogenesis ( 54,55 ). Unlike the lipodystrophic A-ZIP/F-1 mice ( 43 ), Agpat2…”

Section: Discussionmentioning

confidence: 99%

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Cortés

Cautivo

Rong

et al. 2014

Journal of Lipid Research

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“…161 In addition to the phosphorylation-dependent regulation of the 14-3-3/ChREBP interaction, a number of metabolites have been shown to influence this PPI, among them β-hydroxybutyrate (β-HB) and acetoacetate (AcAc). Both β-HB and AcAc have been shown to stabilize 14-3-3 binding to ChREBP, 162 a finding that was later extended to 31 including a convincing structural biology explanation for this activity. 158 A very interesting feature of the interaction between 14-3-3 and ChREBP is that it also employs a phosphorylation-independent binding mechanism.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 97%

Modulators of Protein–Protein Interactions

et al. 2014

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Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

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Metabolite Regulation of Nucleo-cytosolic Trafficking of Carbohydrate Response Element-binding Protein (ChREBP)

Cited by 44 publications

References 24 publications

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Modulators of Protein–Protein Interactions

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