Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate

Terytty Yang Li, Lintao Song, Yu Sun, Jingyi Li, Cong Yi, Sin Man Lam, Dijin Xu, Linkang Zhou, Xiaotong Li, Ying Yang, Chen-Song Zhang, Changchuan Xie, Xi Huang, Guanghou Shui, Shu-Yong Lin, Karen Reue and Sheng-Cai Lin ()
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Terytty Yang Li: Xiamen University
Lintao Song: Xiamen University
Yu Sun: Xiamen University
Jingyi Li: Xiamen University
Cong Yi: Zhejiang University, Hangzhou
Sin Man Lam: Chinese Academy of Sciences
Dijin Xu: Tsinghua University
Linkang Zhou: Tsinghua University
Xiaotong Li: Xiamen University
Ying Yang: Xiamen University
Chen-Song Zhang: Xiamen University
Changchuan Xie: Xiamen University
Xi Huang: Xiamen University
Guanghou Shui: Chinese Academy of Sciences
Shu-Yong Lin: Xiamen University
Karen Reue: David Geffen School of Medicine at University of California
Sheng-Cai Lin: Xiamen University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues. However, how signaling networks sense fatty acids and connect to the stimulation of lipid synthesis remains elusive. Here, we show that homozygous knock-in mice carrying a point mutation at the Ser86 phosphorylation site of acetyltransferase Tip60 (Tip60 SA/SA ) display remarkably reduced body fat mass, and Tip60 SA/SA females fail to nurture pups to adulthood due to severely reduced milk TAGs. Mechanistically, fatty acids stimulate Tip60-dependent acetylation and endoplasmic reticulum translocation of phosphatidic acid phosphatase lipin 1 to generate diacylglycerol for TAG synthesis, which is repressed by deacetylase Sirt1. Inhibition of Tip60 activity strongly blocks fatty acid-induced TAG synthesis while Sirt1 suppression leads to increased adiposity. Genetic analysis of loss-of-function mutants in Saccharomyces cerevisiae reveals a requirement of ESA1, yeast ortholog of Tip60, in TAG accumulation. These findings uncover a conserved mechanism linking fatty acid sensing to fat synthesis.

Date: 2018
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DOI: 10.1038/s41467-018-04363-w

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