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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.

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LSD1 inhibition activates genes for energy expenditure and mitochondrial metabolism in adipocytes.(a) Summarized illustration of co-target genes. Co-target genes , associated with energy expenditure and mitochondrial metabolism, are shown with cellular localization of the gene products. (b) Expression levels of LSD1 target genes under LSD1-KD (red bars) and BHC80-KD (blue bars). Quantitative RT–PCR values were normalized to the expression levels of the 36B4 gene, and are shown as the fold difference against control siRNA-introduced samples (black bars). (c) Expression levels of LSD1 target genes after TC (orange bars) or SLIs (S2101 (red bars), S2107 (blue bars), S2111 (white bars)) treatment. TC and SLIs were used at the concentrations of 10−4 M and 10−5 M, respectively. Values are shown as the fold difference against vehicle-treated samples (black bars). (d) The knockdown of LSD1 using an alternative siRNA (LSD1#2). (e) The effect of LSD1 siRNA#2 on the expression of newly identified LSD1-target genes. Values are shown as the fold difference against control siRNA-introduced samples (black bars). All histogram data are means±s.d. of triplicate results. *P<0.05, **P<0.01 versus control by Student's t-test.
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f2: LSD1 inhibition activates genes for energy expenditure and mitochondrial metabolism in adipocytes.(a) Summarized illustration of co-target genes. Co-target genes , associated with energy expenditure and mitochondrial metabolism, are shown with cellular localization of the gene products. (b) Expression levels of LSD1 target genes under LSD1-KD (red bars) and BHC80-KD (blue bars). Quantitative RT–PCR values were normalized to the expression levels of the 36B4 gene, and are shown as the fold difference against control siRNA-introduced samples (black bars). (c) Expression levels of LSD1 target genes after TC (orange bars) or SLIs (S2101 (red bars), S2107 (blue bars), S2111 (white bars)) treatment. TC and SLIs were used at the concentrations of 10−4 M and 10−5 M, respectively. Values are shown as the fold difference against vehicle-treated samples (black bars). (d) The knockdown of LSD1 using an alternative siRNA (LSD1#2). (e) The effect of LSD1 siRNA#2 on the expression of newly identified LSD1-target genes. Values are shown as the fold difference against control siRNA-introduced samples (black bars). All histogram data are means±s.d. of triplicate results. *P<0.05, **P<0.01 versus control by Student's t-test.

Mentions: By quantitative RT–PCR analyses, we confirmed that important regulators of energy metabolism (Fig. 2a), such as PPARγ coactivator-1α (PGC-1α), pyruvate dehydrogenase kinase 4 (PDK4), protein kinase A regulatory subunit 2 alpha (RIIalpha) and adipose triglyceride lipase (ATGL), were significantly upregulated (Fig. 2b,c;Supplementary Data 1). These gene products have been reported to have key roles in mitochondrial energy production and/or lipid mobilization24252627. Among them, elevated expression of PGC-1α is a hallmark of brown adipose tissue (BAT), which is specialized for consumptive metabolism for the purpose of thermogenesis28. Consistently, LSD1 inhibition induced the expression of fatty acid transporter 1 (FATP1), a critical regulator of BAT metabolism (Fig. 2b,c)2930. The selective upregulation of the group of energy-expenditure genes was confirmed by the use of alternative siRNA against LSD1 (Fig. 2d,e). We also noticed that LSD1 inhibition did not affect the expression of the key adipogenic factors as well as the drivers of brown adipogenesis (Supplementary Table S1).


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)

LSD1 inhibition activates genes for energy expenditure and mitochondrial metabolism in adipocytes.(a) Summarized illustration of co-target genes. Co-target genes , associated with energy expenditure and mitochondrial metabolism, are shown with cellular localization of the gene products. (b) Expression levels of LSD1 target genes under LSD1-KD (red bars) and BHC80-KD (blue bars). Quantitative RT–PCR values were normalized to the expression levels of the 36B4 gene, and are shown as the fold difference against control siRNA-introduced samples (black bars). (c) Expression levels of LSD1 target genes after TC (orange bars) or SLIs (S2101 (red bars), S2107 (blue bars), S2111 (white bars)) treatment. TC and SLIs were used at the concentrations of 10−4 M and 10−5 M, respectively. Values are shown as the fold difference against vehicle-treated samples (black bars). (d) The knockdown of LSD1 using an alternative siRNA (LSD1#2). (e) The effect of LSD1 siRNA#2 on the expression of newly identified LSD1-target genes. Values are shown as the fold difference against control siRNA-introduced samples (black bars). All histogram data are means±s.d. of triplicate results. *P<0.05, **P<0.01 versus control by Student's t-test.
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Related In: Results  -  Collection

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f2: LSD1 inhibition activates genes for energy expenditure and mitochondrial metabolism in adipocytes.(a) Summarized illustration of co-target genes. Co-target genes , associated with energy expenditure and mitochondrial metabolism, are shown with cellular localization of the gene products. (b) Expression levels of LSD1 target genes under LSD1-KD (red bars) and BHC80-KD (blue bars). Quantitative RT–PCR values were normalized to the expression levels of the 36B4 gene, and are shown as the fold difference against control siRNA-introduced samples (black bars). (c) Expression levels of LSD1 target genes after TC (orange bars) or SLIs (S2101 (red bars), S2107 (blue bars), S2111 (white bars)) treatment. TC and SLIs were used at the concentrations of 10−4 M and 10−5 M, respectively. Values are shown as the fold difference against vehicle-treated samples (black bars). (d) The knockdown of LSD1 using an alternative siRNA (LSD1#2). (e) The effect of LSD1 siRNA#2 on the expression of newly identified LSD1-target genes. Values are shown as the fold difference against control siRNA-introduced samples (black bars). All histogram data are means±s.d. of triplicate results. *P<0.05, **P<0.01 versus control by Student's t-test.
Mentions: By quantitative RT–PCR analyses, we confirmed that important regulators of energy metabolism (Fig. 2a), such as PPARγ coactivator-1α (PGC-1α), pyruvate dehydrogenase kinase 4 (PDK4), protein kinase A regulatory subunit 2 alpha (RIIalpha) and adipose triglyceride lipase (ATGL), were significantly upregulated (Fig. 2b,c;Supplementary Data 1). These gene products have been reported to have key roles in mitochondrial energy production and/or lipid mobilization24252627. Among them, elevated expression of PGC-1α is a hallmark of brown adipose tissue (BAT), which is specialized for consumptive metabolism for the purpose of thermogenesis28. Consistently, LSD1 inhibition induced the expression of fatty acid transporter 1 (FATP1), a critical regulator of BAT metabolism (Fig. 2b,c)2930. The selective upregulation of the group of energy-expenditure genes was confirmed by the use of alternative siRNA against LSD1 (Fig. 2d,e). We also noticed that LSD1 inhibition did not affect the expression of the key adipogenic factors as well as the drivers of brown adipogenesis (Supplementary Table S1).

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