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

• DOI: 10.1038/s41467-018-04363-w
• Publication Date: 2018-05-09T10:26:35Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; Saccharomyces cerevisiae Proteins; Science; Phosphatidate Phosphatase; Saccharomyces cerevisiae; Endoplasmic Reticulum; Article; Lysine Acetyltransferase 5; Mice; 03 medical and health sciences; Sirtuin 1; Animals; Triglycerides; Histone Acetyltransferases; Mice, Knockout; Q; Fatty Acids; Nuclear Proteins; Acetylation; Mice, Inbred C57BL; Kinetics; Trans-Activators; Female; Fat metabolism

AbstractObesity 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.