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

Terytty Yang Li,Sin Man Lam,Shu-Yong Lin,Sheng-Cai Lin,Yu Sun,Linkang Zhou,Lintao Song,Guanghou Shui,Dijin Xu,Cong Yi,Changchuan Xie,Karen Reue,Chen-Song Zhang,Xi Huang,Jingyi Li,Ying Yang,Xiaotong Li

doi:10.1038/s41467-018-04363-w

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 (Tip60SA/SA) display remarkably reduced body fat mass, and Tip60SA/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.

Highlights

Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues
The lower body weight in Tip60SA/SA mice was associated with smaller fat depots as well as reduced adipocyte size compared to WT (Fig. 1d–g and Supplementary Fig. 1g–i)
Tip60SA/SA mice were resistant to high-fat diet (HFD)-induced increases in plasma glucose and insulin (Fig. 1j, k), and exhibited greater glucose tolerance and insulin sensitivity as demonstrated by glucose tolerance test (GTT) and insulin tolerance test (ITT) (Fig. 1l–o)

Summary

Introduction

Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues. Genetic analysis of lossof-function mutants in Saccharomyces cerevisiae reveals a requirement of ESA1, yeast ortholog of Tip[60], in TAG accumulation. These findings uncover a conserved mechanism linking fatty acid sensing to fat synthesis. TAG biosynthesis occurs primarily via the glycerol-3phosphate pathway, through the action of conserved enzymes including glycerol-3-phosphate acyltransferases (GPATs), 1acylglycerol-3-phosphate acyltransferases (AGPATs), phosphatidic acid phosphohydrolases (PAPs)/lipins, and diacylglycerol acyltransferases (DGATs). It needs to translocate from cytosol to endoplasmic reticulum (ER) membranes, whereby the hydrophobic phospholipids and neutral lipids are synthesized[2] to catalyze the PAP reaction How this translocalization process is achieved and regulated in response to increased availability of fatty acids remains poorly understood. The physiological functions of Tip[60], especially in metabolic control of adult animals in vivo, are basically unknown due to the early embryonic lethality caused by disruption of Tip[60] gene[17]

Methods

Results

Conclusion