Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1.
JCI Insight
; 6(17)2021 09 08.
Article
en En
| MEDLINE
| ID: mdl-34314389
ABSTRACT
Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPß and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
ARN
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Regulación de la Expresión Génica
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Genes Mitocondriales
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Hígado Graso
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Histona Demetilasas
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Factores de Crecimiento de Fibroblastos
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Hígado
Límite:
Animals
Idioma:
En
Año:
2021
Tipo del documento:
Article