Journal Article

Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1

Paraiso, Kitt, Cheng, Haibo, Sun, Qiushi, Fang, Zhuyuan, Yang, Qin, Blitz, Ira L., Cho, Ken W.Y., Ye, Xiaolong, Tang, Lingyi, Du, Kang, Wang, Ping H., Liu, Zhengxia, Seldin, Marcus, Wang, Xiaorong, Huang, Lan, Cao, Yang, Yuan, Fang, Yu, Clinton, Fang, Yuan, Chen, Yumay, Chen, Hank, Lu, Xiang

2021

Overview

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 GABPβ 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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Animals / Biosynthesis / Body fat / Cells, Cultured / DNA methylation / Endocrinology / Epigenesis, Genetic / Epigenetics / Fatty liver / Fatty Liver - genetics / Fatty Liver - metabolism / Fatty Liver - pathology / Fibroblast Growth Factors - biosynthesis / Fibroblast Growth Factors - genetics / Gene expression / Gene Expression Regulation / Gene regulation / Genes, Mitochondrial - genetics / Genomes / Glucose tolerance / Histone Demethylases - biosynthesis / Histone Demethylases - genetics / Histones / Homeostasis / Liver / Liver - metabolism / Liver - pathology / Metabolism / Metabolites / Mice / Mitochondria / Mitochondrial DNA / NAD / Phosphorylation / Proteins / RNA - genetics / Signal Transduction / SIRT1 protein / Steatosis / Transcription factors