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; Sheng-Cai Lin

doi:10.1038/s41467-018-04363-w

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

Nat Commun. 2018 May 15;9(1):1916. doi: 10.1038/s41467-018-04363-w.

Authors

Terytty Yang Li¹, Lintao Song¹, Yu Sun¹, Jingyi Li¹, Cong Yi², Sin Man Lam³, Dijin Xu⁴, Linkang Zhou⁴, Xiaotong Li¹, Ying Yang¹, Chen-Song Zhang¹, Changchuan Xie¹, Xi Huang¹, Guanghou Shui³, Shu-Yong Lin¹, Karen Reue⁵, Sheng-Cai Lin⁶

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361102, China.
² School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
³ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100084, China.
⁴ MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
⁵ Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, CA, 90095, USA.
⁶ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361102, China. linsc@xmu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Endoplasmic Reticulum / enzymology*
Endoplasmic Reticulum / genetics
Endoplasmic Reticulum / metabolism
Fatty Acids / metabolism
Female
Histone Acetyltransferases / genetics
Histone Acetyltransferases / metabolism
Kinetics
Lysine Acetyltransferase 5 / genetics
Lysine Acetyltransferase 5 / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phosphatidate Phosphatase / genetics
Phosphatidate Phosphatase / metabolism*
Saccharomyces cerevisiae / enzymology
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Sirtuin 1 / genetics
Sirtuin 1 / metabolism
Trans-Activators / genetics
Trans-Activators / metabolism*
Triglycerides / biosynthesis*
Triglycerides / chemistry

Substances

Fatty Acids
Nuclear Proteins
Saccharomyces cerevisiae Proteins
Trans-Activators
Triglycerides
Esa1 protein, S cerevisiae
Histone Acetyltransferases
Kat5 protein, mouse
Lysine Acetyltransferase 5
Lpin1 protein, mouse
Phosphatidate Phosphatase
Sirt1 protein, mouse
Sirtuin 1

Grants and funding

P01 HL090553/HL/NHLBI NIH HHS/United States