De novo lipogenesis (DNL) is the metabolic pathway primarily utilized by the liver and adipose tissue to synthesize fatty acids from excess carbohydrates. An increased rate of DNL is observed in many characteristically "Western" diseases of affluence, such as type 2 diabetes and cardiovascular disease. Metabolic changes can lead to an altered expression of DNL genes through the acetylation of histones, the proteins that package DNA, but the molecular details remain poorly understood. A collaboration between the IBS and the Institute for Advanced Biosciences (IAB) has revealed that the metabolic enzymes NME1 and NME2 (collectively called NME1/2) play a key role in this epigenetic regulation. NME1/2 is best known for its role in balancing nucleotide proportions in the cell by transferring a phosphate group from ATP to a nucleoside diphosphate. Biochemical, crystallographic and native mass spectrometry data revealed that NME1/2 binds to acetyl-CoA, a key metabolite for histone acetylation, competitively with ATP. Remarkably, when fed a high-fat diet, a mouse knockout model with greatly reduced NME1/2 levels exhibited excessive triglyceride synthesis and liver steatosis (fat buildup). In liver cells, NME1/2 was found to mediate a gene transcriptional response to a high-fat diet via the targeted acetylation of histones that inhibits fatty acid accumulation by repressing genes encoding key transcription factors involved in DNL and fatty acid metabolism. These findings shed important light on how DNL is regulated and reveal a previously unsuspected level of cross-talk between metabolic and epigenetic pathways.
Nucleoside Diphosphate Kinases 1 and 2 regulate a liver protective response to a high-fat diet. Iuso D, Garcia-Saez I, Couté Y, Yamaryo-Botté Y, Boeri Erba E, Adrait A, Zeaiter N, Tokarska-Schlattner M, Macek Jilkova Z, Boussouar F, Barral S, Signor L, Couturier K, Hajmirza A, Chuffart F, Bourova-Flin E, Vitte A-L, Bargier L, Puthier D, Decaens T, Rousseaux S, Botté C, Schlattner U, Petosa C, Khochbin S. Science Advances 2023 ; 9(36):eadh0140.
Contact : Carlo Petosa (IBS/Epigenetics and molecular pathways Group)