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

Nature Communications
Terytty Yang LiSheng-Cai Lin

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.

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Citations

Feb 23, 2020·Experimental & Molecular Medicine·Minjung ChaeJi-Yong Jung
Jun 10, 2020·Brain : a Journal of Neurology·Ana CascalhoRose E Goodchild
Jun 21, 2019·Journal of Cellular and Molecular Medicine·Xin Shi, Mingfu Fan
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Oct 16, 2021·Molecular Biology Reports·Nurdan Gönül BaltacıHarun Budak
Nov 2, 2021·American Journal of Physiology. Endocrinology and Metabolism·Saori KakehiHirotaka Watada

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Methods Mentioned

BETA
acetylation
acetylating
transfection
PCR
electrophoresis
immunoprecipitation
Fluorescence

Software Mentioned

Graphpad Prism
MobiDB
SPSS Statistics
ANONA
Adobe Photoshop

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