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FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure.

Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, Umehara T, Yokoyama S, Kosai K, Nakao M - Nat Commun (2012)

Bottom Line: The lysine-specific demethylase-1 (LSD1) is a unique nuclear protein that utilizes flavin adenosine dinucleotide (FAD) as a cofactor.We find that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration.In the adipose tissues from mice on a high-fat diet, expression of LSD1-target genes is reduced, compared with that in tissues from mice on a normal diet, which can be reverted by suppressing LSD1 function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, the Global Center of Excellence 'Cell Fate Regulation Research and Education Unit', Kumamoto University, 860-0811, Japan. s-hino@kumamoto-u.ac.jp

ABSTRACT
Environmental factors such as nutritional state may act on the epigenome that consequently contributes to the metabolic adaptation of cells and the organisms. The lysine-specific demethylase-1 (LSD1) is a unique nuclear protein that utilizes flavin adenosine dinucleotide (FAD) as a cofactor. Here we show that LSD1 epigenetically regulates energy-expenditure genes in adipocytes depending on the cellular FAD availability. We find that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration. In the adipose tissues from mice on a high-fat diet, expression of LSD1-target genes is reduced, compared with that in tissues from mice on a normal diet, which can be reverted by suppressing LSD1 function. Our data suggest a novel mechanism where LSD1 regulates cellular energy balance through coupling with cellular FAD biosynthesis.

Show MeSH
Schematic model of LSD1 function in the metabolic gene regulation.Schematic model for the epigenetic regulation of energy metabolism by LSD1. FAD-dependent LSD1 facilitates metabolic changes through the repression of energy-expenditure genes via H3K4 demethylation. This pathway may be influenced by nutrients and/or fluctuating FAD level, implicating the link between energetic information and the epigenome.
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f8: Schematic model of LSD1 function in the metabolic gene regulation.Schematic model for the epigenetic regulation of energy metabolism by LSD1. FAD-dependent LSD1 facilitates metabolic changes through the repression of energy-expenditure genes via H3K4 demethylation. This pathway may be influenced by nutrients and/or fluctuating FAD level, implicating the link between energetic information and the epigenome.

Mentions: One of the key factors in formulating an energy strategy is environmental information such as nutritional availability. As many metabolism-associated genes are epigenetically regulated40, nutrient-driven epigenetic factors may have important roles in forming metabolic phenotypes3. LSD1 is a unique demethylase that does not contain the jumonji domain but as a flavoenzyme does have the FAD-dependent amine oxidase domain1. Our present study clearly indicates that LSD1 negatively regulates energy expenditure that can be reversed by inhibiting LSD1 function and FAD biosynthesis (Fig. 8). Cellular FAD potentiates LSD1 to repress energy-expenditure genes such as PGC-1α through H3K4 demethylation in adipocytes where excess energy is stored as triglycerides. Moreover, our experiments using mature adipocytes and isolated adipose tissues revealed the metabolic state-dependent effects of LSD1 inhibition. Thus, the transcriptional and epigenetic regulation by FAD-dependent LSD1 may be central in nutrient-driven metabolic adaptation.


FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure.

Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, Umehara T, Yokoyama S, Kosai K, Nakao M - Nat Commun (2012)

Schematic model of LSD1 function in the metabolic gene regulation.Schematic model for the epigenetic regulation of energy metabolism by LSD1. FAD-dependent LSD1 facilitates metabolic changes through the repression of energy-expenditure genes via H3K4 demethylation. This pathway may be influenced by nutrients and/or fluctuating FAD level, implicating the link between energetic information and the epigenome.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3316891&req=5

f8: Schematic model of LSD1 function in the metabolic gene regulation.Schematic model for the epigenetic regulation of energy metabolism by LSD1. FAD-dependent LSD1 facilitates metabolic changes through the repression of energy-expenditure genes via H3K4 demethylation. This pathway may be influenced by nutrients and/or fluctuating FAD level, implicating the link between energetic information and the epigenome.
Mentions: One of the key factors in formulating an energy strategy is environmental information such as nutritional availability. As many metabolism-associated genes are epigenetically regulated40, nutrient-driven epigenetic factors may have important roles in forming metabolic phenotypes3. LSD1 is a unique demethylase that does not contain the jumonji domain but as a flavoenzyme does have the FAD-dependent amine oxidase domain1. Our present study clearly indicates that LSD1 negatively regulates energy expenditure that can be reversed by inhibiting LSD1 function and FAD biosynthesis (Fig. 8). Cellular FAD potentiates LSD1 to repress energy-expenditure genes such as PGC-1α through H3K4 demethylation in adipocytes where excess energy is stored as triglycerides. Moreover, our experiments using mature adipocytes and isolated adipose tissues revealed the metabolic state-dependent effects of LSD1 inhibition. Thus, the transcriptional and epigenetic regulation by FAD-dependent LSD1 may be central in nutrient-driven metabolic adaptation.

Bottom Line: The lysine-specific demethylase-1 (LSD1) is a unique nuclear protein that utilizes flavin adenosine dinucleotide (FAD) as a cofactor.We find that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration.In the adipose tissues from mice on a high-fat diet, expression of LSD1-target genes is reduced, compared with that in tissues from mice on a normal diet, which can be reverted by suppressing LSD1 function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, the Global Center of Excellence 'Cell Fate Regulation Research and Education Unit', Kumamoto University, 860-0811, Japan. s-hino@kumamoto-u.ac.jp

ABSTRACT
Environmental factors such as nutritional state may act on the epigenome that consequently contributes to the metabolic adaptation of cells and the organisms. The lysine-specific demethylase-1 (LSD1) is a unique nuclear protein that utilizes flavin adenosine dinucleotide (FAD) as a cofactor. Here we show that LSD1 epigenetically regulates energy-expenditure genes in adipocytes depending on the cellular FAD availability. We find that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration. In the adipose tissues from mice on a high-fat diet, expression of LSD1-target genes is reduced, compared with that in tissues from mice on a normal diet, which can be reverted by suppressing LSD1 function. Our data suggest a novel mechanism where LSD1 regulates cellular energy balance through coupling with cellular FAD biosynthesis.

Show MeSH