期刊
JCI INSIGHT
卷 6, 期 17, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.147692
关键词
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资金
- NIH [R01DK100385, R01DK121146, R01GM074830, R01GM126395]
- Chinese Natural Science Foundation [81873258]
- Priority Academic program Development of Jiangsu Higher Education Institutions [2018-87]
- National Science Foundation [1755214]
- Jiangsu Province Hospital of Chinese Medicine
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [1755214] Funding Source: National Science Foundation
LSD1 regulates mitochondrial function and hepatokine production by modulating histone methylation and NAD+ synthesis. Deletion of LSD1 in mice reduces mitochondrial function in the liver but protects against diet-induced hepatic steatosis and glucose intolerance, partially due to the induction of the hepatokine FGF21.
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 GABP beta and PGC-1 alpha, 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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