Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 Jan 2024
02 Jan 2024
Historique:
received:
19
06
2023
accepted:
11
12
2023
medline:
4
1
2024
pubmed:
4
1
2024
entrez:
3
1
2024
Statut:
epublish
Résumé
Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.
Identifiants
pubmed: 38167725
doi: 10.1038/s41467-023-44364-y
pii: 10.1038/s41467-023-44364-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
45Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 450149205-TRR333/1 P15
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SCHL2276/2-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 450149205-TRR333/1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1328
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : FI 2476/1-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 450149205-TRR333/1
Informations de copyright
© 2024. The Author(s).
Références
Postic, C. & Girard, J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 118, 829–838 (2008).
pubmed: 18317565
pmcid: 2254980
doi: 10.1172/JCI34275
Perry, R. J., Samuel, V. T., Petersen, K. F. & Shulman, G. I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510, 84–91 (2014).
pubmed: 24899308
pmcid: 4489847
doi: 10.1038/nature13478
Chong, M. F., Fielding, B. A. & Frayn, K. N. Metabolic interaction of dietary sugars and plasma lipids with a focus on mechanisms and de novo lipogenesis. Proc. Nutr. Soc. 66, 52–59 (2007).
pubmed: 17343772
doi: 10.1017/S0029665107005290
Palmisano, B. T., Zhu, L. & Stafford, J. M. Role of estrogens in the regulation of liver lipid metabolism. Adv. Exp. Med. Biol. 1043, 227–256 (2017).
pubmed: 29224098
pmcid: 5763482
doi: 10.1007/978-3-319-70178-3_12
Yao, X. et al. Regulation of fatty acid composition and lipid storage by thyroid hormone in mouse liver. Cell Biosci. 4, 38 (2014).
pubmed: 25105012
pmcid: 4124172
doi: 10.1186/2045-3701-4-38
Antherieu, S., Rogue, A., Fromenty, B., Guillouzo, A. & Robin, M. A. Induction of vesicular steatosis by amiodarone and tetracycline is associated with up-regulation of lipogenic genes in HepaRG cells. Hepatology 53, 1895–1905 (2011).
pubmed: 21391224
doi: 10.1002/hep.24290
Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J. Hepatol. 69, 896–904 (2018).
pubmed: 29886156
doi: 10.1016/j.jhep.2018.05.036
Kim, C. W. et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 26, 394–406.e396 (2017).
pubmed: 28768177
pmcid: 5603267
doi: 10.1016/j.cmet.2017.07.009
Loomba, R. et al. GS-0976 Reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 155, 1463–1473.e1466 (2018).
pubmed: 30059671
doi: 10.1053/j.gastro.2018.07.027
Loomba, R. et al. TVB-2640 (FASN Inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology 161, 1475–1486 (2021).
Calle, R. A. et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Nat. Med. 27, 1836–1848 (2021).
pubmed: 34635855
doi: 10.1038/s41591-021-01489-1
Palomer, X., Pizarro-Delgado, J., Barroso, E. & Vazquez-Carrera, M. Palmitic and oleic acid: the yin and yang of fatty acids in type 2 diabetes mellitus. Trends Endocrinol. Metab. 29, 178–190 (2018).
pubmed: 29290500
doi: 10.1016/j.tem.2017.11.009
Marcelino, H. et al. A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: a Randle cycle favoring fat storage. Diabetes 62, 362–372 (2013).
pubmed: 22961086
pmcid: 3554390
doi: 10.2337/db12-0255
Akazawa, Y. et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J. Hepatol. 52, 586–593 (2010).
pubmed: 20206402
pmcid: 2847010
doi: 10.1016/j.jhep.2010.01.003
Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).
pubmed: 18805087
pmcid: 2728618
doi: 10.1016/j.cell.2008.07.048
Chirala, S. S. et al. Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc. Natl Acad. Sci. USA 100, 6358–6363 (2003).
pubmed: 12738878
pmcid: 164451
doi: 10.1073/pnas.0931394100
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
pubmed: 27535533
pmcid: 5018207
doi: 10.1038/nature19057
Roumans, K. H. M. et al. Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance. Nat. Commun. 11, 1891 (2020).
pubmed: 32312974
pmcid: 7170906
doi: 10.1038/s41467-020-15684-0
Murphy, E. J. Stable isotope methods for the in vivo measurement of lipogenesis and triglyceride metabolism. J. Anim. Sci. 84, E94–E104 (2006).
pubmed: 16582096
doi: 10.2527/2006.8413_supplE94x
Aarsland, A. & Wolfe, R. R. Hepatic secretion of VLDL fatty acids during stimulated lipogenesis in men. J. Lipid Res 39, 1280–1286 (1998).
pubmed: 9643360
doi: 10.1016/S0022-2275(20)32553-0
Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat. Commun. 4, 1528 (2013).
pubmed: 23443556
doi: 10.1038/ncomms2537
Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).
pubmed: 15864352
pmcid: 1087172
doi: 10.1172/JCI23621
Lee, W. N. et al. In vivo measurement of fatty acids and cholesterol synthesis using D2O and mass isotopomer analysis. Am. J. Physiol. 266, E699–E708 (1994).
pubmed: 8203508
O’Hea, E. K. & Leveille, G. A. Significance of adipose tissue and liver as sites of fatty acid synthesis in the pig and the efficiency of utilization of various substrates for lipogenesis. J. Nutr. 99, 338–344 (1969).
pubmed: 5350989
doi: 10.1093/jn/99.3.338
Marra, F. & Svegliati-Baroni, G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 68, 280–295 (2018).
pubmed: 29154964
doi: 10.1016/j.jhep.2017.11.014
Yahagi, N. et al. A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. J. Biol. Chem. 274, 35840–35844 (1999).
pubmed: 10585468
doi: 10.1074/jbc.274.50.35840
Dentin, R. et al. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J. Clin. Invest. 115, 2843–2854 (2005).
pubmed: 16184193
pmcid: 1224299
doi: 10.1172/JCI25256
Sanders, T. A., Sullivan, D. R., Reeve, J. & Thompson, G. R. Triglyceride-lowering effect of marine polyunsaturates in patients with hypertriglyceridemia. Arteriosclerosis 5, 459–465 (1985).
pubmed: 4038159
doi: 10.1161/01.ATV.5.5.459
Skulas-Ray, A. C. et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 140, e673–e691 (2019).
pubmed: 31422671
doi: 10.1161/CIR.0000000000000709
Blaton, V. et al. Effect of polyunsaturated isocaloric fat diets on plasma lipids, apolipoproteins and fatty acids. Atherosclerosis 53, 9–20 (1984).
pubmed: 6497946
doi: 10.1016/0021-9150(84)90100-X
Sekiya, M. et al. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology 38, 1529–1539 (2003).
pubmed: 14647064
doi: 10.1016/j.hep.2003.09.028
Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 64, 1167–1175 (2016).
pubmed: 26780287
doi: 10.1016/j.jhep.2016.01.002
Mitsche, M. A., Hobbs, H. H. & Cohen, J. C. Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J. Biol. Chem. 293, 6958–6968 (2018).
pubmed: 29555681
pmcid: 5936833
doi: 10.1074/jbc.RA118.002333
Luukkonen, P. K. et al. Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 76, 526–535 (2022).
pubmed: 34710482
pmcid: 8852745
doi: 10.1016/j.jhep.2021.10.013
Lee, C. H., Fu, Y., Yang, S. J. & Chi, C. C. Effects of omega-3 polyunsaturated fatty acid supplementation on non-alcoholic fatty liver: a systematic review and meta-analysis. Nutrients 12 (2020).
Capanni, M. et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharm. Ther. 23, 1143–1151 (2006).
doi: 10.1111/j.1365-2036.2006.02885.x
Spadaro, L. et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig. Liver Dis. 40, 194–199 (2008).
pubmed: 18054848
doi: 10.1016/j.dld.2007.10.003
Bjermo, H. et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am. J. Clin. Nutr. 95, 1003–1012 (2012).
pubmed: 22492369
doi: 10.3945/ajcn.111.030114
Argo, C. K. et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J. Hepatol. 62, 190–197 (2015).
pubmed: 25195547
doi: 10.1016/j.jhep.2014.08.036
Manson, J. E. et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl. J. Med. 380, 23–32 (2019).
pubmed: 30415637
doi: 10.1056/NEJMoa1811403
Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).
pubmed: 30415628
doi: 10.1056/NEJMoa1812792
Nicholls, S. J. et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 324, 2268–2280 (2020).
pubmed: 33190147
pmcid: 7667577
doi: 10.1001/jama.2020.22258
Lin, H. P. et al. Destabilization of fatty acid synthase by acetylation inhibits de novo lipogenesis and tumor cell growth. Cancer Res. 76, 6924–6936 (2016).
pubmed: 27758890
pmcid: 5135623
doi: 10.1158/0008-5472.CAN-16-1597
James, A. M. et al. Non-enzymatic N-acetylation of lysine residues by AcetylCoA often occurs via a proximal s-acetylated thiol intermediate sensitive to glyoxalase II. Cell Rep. 18, 2105–2112 (2017).
pubmed: 28249157
pmcid: 6381604
doi: 10.1016/j.celrep.2017.02.018
Ortega-Prieto, P. & Postic, C. Carbohydrate sensing through the transcription factor ChREBP. Front Genet 10, 472 (2019).
pubmed: 31275349
pmcid: 6593282
doi: 10.3389/fgene.2019.00472
Bowers, M. et al. FASN-dependent lipid metabolism links neurogenic stem/progenitor cell activity to learning and memory deficits. Cell Stem Cell 27, 98–109 e111 (2020).
pubmed: 32386572
doi: 10.1016/j.stem.2020.04.002
Niwa, H. et al. ChREBP rather than SHP regulates hepatic VLDL secretion. Nutrients 10 (2018).
Rong, X. et al. ER phospholipid composition modulates lipogenesis during feeding and in obesity. J. Clin. Invest. 127, 3640–3651 (2017).
pubmed: 28846071
pmcid: 5617651
doi: 10.1172/JCI93616
Sagar, G. D. et al. Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol. Cell Biol. 27, 4774–4783 (2007).
pubmed: 17452445
pmcid: 1951476
doi: 10.1128/MCB.00283-07
Wang, H. et al. Role of histone H2A ubiquitination in polycomb silencing. Nature 431, 873–878 (2004).
pubmed: 15386022
doi: 10.1038/nature02985
Song, S. et al. The HDAC3 enzymatic activity regulates skeletal muscle fuel metabolism. J. Mol. Cell Biol. 11, 133–143 (2019).
pubmed: 30428023
doi: 10.1093/jmcb/mjy066
Mano, T., Suzuki, T., Tsuji, S. & Iwata, A. Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregates. PLoS ONE 9, e111277 (2014).
pubmed: 25380050
pmcid: 4224383
doi: 10.1371/journal.pone.0111277
Bergman, A. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a liver-targeting acetyl-CoA Carboxylase inhibitor (PF-05221304): a three-part randomized phase 1 study. Clin. Pharm. Drug Dev. 9, 514–526 (2020).
doi: 10.1002/cpdd.782
Matyash, V., Liebisch, G., Kurzchalia, T. V., Shevchenko, A. & Schwudke, D. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J. Lipid Res. 49, 1137–1146 (2008).
pubmed: 18281723
pmcid: 2311442
doi: 10.1194/jlr.D700041-JLR200
Barr, J. et al. Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression. J. Proteome Res. 11, 2521–2532 (2012).
pubmed: 22364559
pmcid: 3321123
doi: 10.1021/pr201223p
Su, B. et al. A DMS shotgun lipidomics workflow application to facilitate high-throughput, comprehensive lipidomics. J. Am. Soc. Mass Spectrom. 32, 2655–2663 (2021).
pubmed: 34637296
pmcid: 8985811
doi: 10.1021/jasms.1c00203
Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441–453 (2016).
pubmed: 26853749
doi: 10.1016/j.cmet.2016.01.006
McDonald, J. G., Thompson, B. M., McCrum, E. C. & Russell, D. W. Extraction and analysis of sterols in biological matrices by high performance liquid chromatography electrospray ionization mass spectrometry. Methods Enzymol. 432, 145–170 (2007).
pubmed: 17954216
doi: 10.1016/S0076-6879(07)32006-5
Dole, V. P. A relation between non-esterified fatty acids in plasma and the metabolism of glucose. J. Clin. Invest. 35, 150–154 (1956).
pubmed: 13286333
pmcid: 438791
doi: 10.1172/JCI103259
Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008).
pubmed: 18772430
doi: 10.1126/science.1161269
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).
pubmed: 32881101
doi: 10.1002/pro.3943
Shevchenko, A., Tomas, H., Havlis, J., Olsen, J. V. & Mann, M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat. Protoc. 1, 2856–2860 (2006).
pubmed: 17406544
doi: 10.1038/nprot.2006.468
Orsburn, B. C. Proteome Discoverer-A community enhanced data processing suite for protein informatics. Proteomes 9 (2021).
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
pubmed: 27348712
doi: 10.1038/nmeth.3901