The Biological Function And Molecular Mechanism For The Regulation Of Fat Synthesis By Tip60

Obesity is characterized by excessive fatty acid(FA)conversion to triacylglycerol(TAG)and fat accumulation in adipose tissues.However,how signaling networks sense FAs and connect to the stimulation of lipid synthesis is poorly understood.Here,we show that homozygous knock-in mice carrying a single point mutation of acetyltransferase Tip60 at the Ser86 phosphorylation site(Tip60SA/SA)display drastic reduction(up to 60%)of body fat mass.In addition,the Tip60SA/SA mice are virtually immune to high-fat diet(HFD)-induced obesity and metabolic disorders such as hepatosteatosis and insulin resistance,and Tip60SA/SA females fail to nurture pups to adulthood due to severely reduced milk TAGs.Mechanistically,FAs or HFD stimulates Tip60-dependent acetylation of phosphatidic acid(PA)phosphatase lipin 1,which catalyzes the dephosphorylation of PA to diacylglycerol(DAG),the penultimate step in TAG biosynthesis.After acetylation,lipin 1 translocates from cytosol to endoplasmic reticulum(ER)-associated membranes,allowing for the production of neutral lipids therein.The ER translocation of lipin 1,together with TAG synthesis,is repressed by SIRT1,which is also responsible for lipin 1 deacetylation.Genetic analysis of loss-of-function mutants in Saccharomyces cerevisiae reveals a requirement of ESA1,yeast ortholog of Tip60,as well as ESA1-mediated acetylation of PAH1 yeast ortholog of lipin 1,in TAG accumulation.These results highlight a conserved gate-keeping role of Tip60 as well as lipin 1 acetylation in fat synthesis,and proper modulation of Tip60 activity might be a promising strategy for the alleviation of obesity.