https://pubmed.ncbi.nlm.nih.gov/31296099/
Conclusions: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.
https://www.caymanchem.com/news/sphingosine-1-phosphate-vs-ceramide
( Tämä aihe on jatkoa K-vitamiiniaineenvaihduntaa käsiteleviin muistiinpanoihini, koska Kvitamiini on sfingomyeliinin aineenvaihdunnan alku ja pääte kohdissa vaikuttava koentsyymi. Merkitsin linkin STUK kirjaani numero 3 Säteilyn käyttö, sivulle 182 ja piirsin artikkelin kaavakuvat myös muistiin. Asetan linkin Blogiin , jossa kirjoitan eri molekyleistä rasva-aineenvaihdunnan alueelta.)
Sittaatti netistä: Aihe on käsitelty auringon UV- säteilyn polttovaikutuksista katsoen. Se vaikuttaa jonisoivasti ja tekee vapaita radikaaleja. ne taas vapauttavat ihon pintakerroksen sfingomyeliinistä solunsisisiä keramideja ja ne aihuttavat reaktiosarjan, joka johtaa lopulta slun kuolemaan. Tässä keramidien katabolisessa tiessä on kuitenkin yksi vaihe, sfingosiini-1-fosfaatin muodostuminen (S1P). Se on molekyyli, josta artikkeli kertoo. Katsotaan mitä sanottavaa hra Brockin konseptissa on mainittuna.
Aluksi toistetaan synoptinen kaava sfinganiinin muodostuksesta alkutekijöistä soluaineenvaihdunnassa: aktivoidusta palmitiinihaposta joka kondensoituu aktivoidun seriiniaminohapon kanssa reaktiossa, jossa tarvitaan apuna mm ravintoperäoisiä vitamiineja entsyymien apuna: K1-vitamiinivaikutusta ja B6 vitamiinia sekä koentsyymi A:ta. Sfingomyeliinin muodostus on hyvin tärkeä ihmisen solukalvoille, varsinkin aivostossa ja hermostossa, myeliinitupessa ja myös ihon suojakerroksissa. Toisaalta sfingomyeliinimetaboliiteista (SMM) tunnetaan myös onkologian alueen aineksia, jotka signaloivat. Sfingomyeliinin hydrolyysissä muodostuu myös sfingosiini (So) ja siitä on suotuisissa oloissa mahdollinen salvage-tie takaisin kohti keramidimuotoa ja uudelleen sfingolipideihin... tai Sfingosiini fosforyloituu: muodostuu S-1-P.
Sfingomyeliinin muodostuksen kartta on "erikoisen tiivisti säädelty suljettu ympyrä" sikäli että siihen johtaa yksi tie ja siitä pääsee ulos vain yhtä tietä normaalisti - poikkeukset ovat harhateitä tavalla tai toisella. Evolutionaalisti ajatellen tämän normaalitien täytyy olla voitokas, koska ihmiskunta vain lisääntyy ja kasvaa täällä auringon alla ja pysyy vedenpitävänä - aikansa, jopa yli sata vuotta joskus. Eri asia, jos ihmiset koettavat pois maaallon suojakerroksista jonisoivaan avaruuteen. luulisi että se vähentää ihmiskunnan keskimääräistä ikää.
Sphingosine-1-Phosphate vs. Ceramide: The Battle of the Burn
Article from 2012-02-01
By Thomas G. Brock, Ph.D.
The luxurious warmth of the sun's rays on the face and shoulders slowly, subtly, gives way to redness and tenderness. Without attention, continued exposure produces a painful burn, followed days later by sloughing of a layer of dead skin tissue. This familiar experience is one demonstration of the ability of ionizing radiation, in the form of ultraviolet light from the sun, to generate reactive oxygen species (ROS) that trigger the release of ceramide within cells, leading to cell death. Remarkably, the effects of ceramide can be diminished by its related metabolite, sphingosine 1-phosphate (S1P). This article introduces these lipids and their complex interrelationship.
Sphingolipids are, like phospholipids, integral components of biological membranes. Ceramide, the simplest of the sphingolipids, is composed of a sphingosine base and an amide-linked acyl chain of variable length. Ceramide can be synthesized de novo in the endoplasmic reticulum through the serine palmitoyl transferase pathway, which involves the production of the intermediate sphinganine and its conversion to the immediate precursor dihydroceramide by ceramide synthases, CerS (Figure 1). Interestingly, CerS was initially identified in yeast as the longevity assurance gene 1 (LAG1), because deletion of LAG1 prolongs the replicative lifespan of Saccharomyces cerevisiae. The mouse homolog of LAG1 is called longevity assurance homolog 1 (LASS1) or upstream of growth and differentiation factor 1 (UOG1). LASS1 activity, which specifically regulates the synthesis of C18-ceramide, determines cell longevity rather than mouse aging, since reduced activity is associated with a proliferative, cancerous phenotype.1
(Katso linkistä KAAVA) ( Alla kuvataan järjestelmän entsyymeitä)
Figure 1. Ceramide synthesis and metabolism
Ceramide can be rapidly released from membrane-associated sphingomyelin by sphingomyelinases (SMase, or sphingomyelin phosphodiesterases). There are several SMases in man, including three neutral SMases that have greatest activity at neutral pH and an acidic SMase (ASMase) that, while active at neutral pH, shows increased functionality in acidic environments. This latter enzyme is abundant in lysosomal membranes but can also be found in plasma membranes associated with lipid rafts. Defects in ASMase cause Niemann-Pick disease, a lysosome storage disease. Lymphoblasts from Niemann-Pick patients fail to respond to ionizing radiation with ceramide generation and apoptosis.2 These abnormalities are reversed by the transfected expression of ASMase, demonstrating the central role of this SMase in radiation-induced apoptosis. Furthermore, ASMase is activated by ROS as well as by peroxynitrite, a product formed from nitric oxide and superoxide.3 Thus, ROS produced by ionizing radiation activates ASMase, causing the production of ceramide.
Ceramide can be de-acylated by ceramidases to give sphingosine (So) plus a carboxylate, and sphingosine in turn can be phosphorylated by sphingosine kinases (SPHK) to produce S1P. S1P is a potent signal transduction-inducing molecule that is involved in such diverse biological processes as cell proliferation, differentiation, migration, and cell survival. There are at least two human ceramidases, an acidic form that is associated with lysosomes and a neutral ceramidase that is associated with the plasma membrane. Similarly, there are two human SPHK forms. SPHK1, the better studied form, is activated by many stimuli, including TGF-β, IL-1β, TNF-α, platelet-derived growth factor, insulin, and LPS. Phosphorylation of Ser311 on SPHK1 by ERK1/2, reversed by PP2A, causes plasma membrane targeting and activation of SPHK1. SPHK1 is best known as a survival, or anti-apoptosis, enzyme with additional positive effects on cell motility and proliferation resulting from the production of S1P. In addition, SPHK1-derived S1P activates endothelium, regulating endothelial barrier homeostasis, primes neutrophils, activates macrophages and promotes phagosome maturation, and increases immune cell motility and function. While some of the actions of SPHK2-derived S1P overlap those of SPHK1, SPHK2 may promote, rather than prevent, apoptosis.
Ceramide is a bioactive lipid which regulates many cell functions, including apoptosis, proliferation, and differentiation. Its biological effects depend on its concentration, the time frame of activation, and the activation or differentiation status of the cell. In addition, ceramide may be produced in one membrane site and trafficked to others, e.g., from the plasma membrane to the mitochondrial membrane.4 Ceramide signals along several pathways, including ceramide-activated protein kinases (e.g., PKC and MEK isoforms) and protein phosphatases (e.g., PP1 and PP2A). This indicates that there is no general pathway of ceramide action, that the specific effects must be evaluated for each cellular situation.
Ionizing radiation-induced ROS activate PKCδ, which phosphorylates ASMase on Ser508 and causes the relocation of ASMase from lysosomes to the plasma membrane, as shown in Figure 2.5 Activated ASMase catalyzes the release of ceramide from lipid raft-associated sphingomyelin (SM) within minutes; additional ceramide production occurs hours later, when, in response to DNA damage, the de novo synthesis pathway is activated. More specifically, DNA damage induces proteasome-dependent processing of CerS1, followed by the translocation of the modified enzyme from the ER to the Golgi and increased ceramide production.6 Within the plasma membrane, the production of ceramide in lipid rafts drives the coalescence of multiple small rafts into ceramide-enriched membrane platforms.7 Within these platforms, ceramide may slowly flip between the inner and outer leaflets of the lipid bilayer and be accessible to intracellular molecules. Ionizing radiation, as well as other forms of stress, activate the SAPK/JNK pathways.8 Specifically, both JNK1 and JNK2 are activated by MAPK8 and MAPK9, which phosphorylate nuclear transcription factors, including c-Jun, Fos, JunB, and ATF2. Also, the JNKs target Bcl-2 family members associated with mitochrondria, driving apoptosis. In addition, ceramide, induced by stresses including radiation, inactivates the PI3K/Akt/Bad pathway, which also facilitates apoptosis.9
S1P was first thought to have its effects intracellularly, acting as a second messenger, interacting with and modulating the activities of specific target proteins. While this certainly happens,10 most current research focuses on the signaling of S1P as a secreted ligand, activating G-protein coupled receptors in an autocrine or paracrine fashion. These receptors were initially identified as EDG (endothelial differentiation gene) receptors and were orphan receptors. With the identification of S1P as a ligand for five of the EDG receptors, these have been renamed: S1P1 (EDG1), S1P2 (EDG5), S1P3 (EDG3), S1P4 (EDG6), and S1P5 (EDG8). S1P1 and S1P3 were first isolated from endothelial cells, while S1P2 was first found on rat brain and vascular smooth muscle cells, S1P4 was found on dendritic cells and S1P5 on rat PC12 (prostate cancer) cells. The five S1P receptors share high sequence identity with the cannabinoid and lysophosphatidic receptors, which are also G-protein coupled receptors for lipid ligands. Through these receptors, S1P regulates cell proliferation, differentiation, stress fiber formation, cell motility and migration, and cell survival.11
Perhaps one of the most exciting effects of S1P relates to its action on lymphocyte trafficking. The concentration of S1P in lymphoid tissues is normally low compared with that of the lymph. Lymphocytes within lymphoid tissues respond to this gradient, through the S1P1 receptor, by migrating from the tissue into the lymph. If the S1P levels within lymphoid nodes are elevated, by inhibition of S1P lyase, inflammation, or by the addition of stable S1P analogs, then lymphocyte egress is blocked. This greatly reduces the number of circulating lymphocytes and diminishes their ability to participate in the immune response. S1P analogs include SEW2871 , FTY720 , and (S)-FTY720-phosphonate. Because of its ability to reduce lymphocytic trafficking, FTY720 is effective in the treatment of multiple sclerosis.
Since ceramide is readily converted to sphingosine, which in turn can give rise to the potent mediator S1P, one might ask if S1P mediates any of the pro-apoptotic actions of ceramide. In fact, ionizing radiation initially downregulates sphingosine kinase 1, impairing the production of S1P.12 Moreover, added S1P has been shown to be a radioprotectant, preventing oocyte apoptosis and male sterility in irradiated mice.13-15 Isolated, proliferating endothelial cells, when irradiated, undergo an early premitotic apoptosis that is dependent on ceramide production in many cells, followed by a delayed death resulting from DNA damage in other cells. S1P protects cells from ceramide-dependent apoptosis but not from DNA damage-induced mitotic death.16 Also, mice maintained on S1P analogs are significantly protected against radiation-induced lung injury.17 It should be noted that these effects are seen over a 6 week period and appear to rely on altered gene expression in response to S1P analogs. Signaling via S1P1, S1P2, and S1P3, the analogs decrease vascular leak through several effects on the cytoskeletal and adhesive properties of endothelial cells.17 In addition, over this prolonged period, radiation increases the expression of both sphingosine kinase isoforms, perhaps suggesting the existence of a delayed protective feedback loop. Taken together, these studies suggest that intervention through S1P is an attractive approach to ameliorating the ceramide-dependent effects of ionizing radiation.
1. Koybasi, S., Senkal, C.E., Sundararaj, K., et al.J. Biol. Chem.279(43), 44311-44319 (2004).
2. Santana, P., Peña, L.A., Haimovitz-Friedman, A., et al.Cell86(2), 189-199 (1996).
3. Corre, I., Niaudet, C., and Paris, F. Mutat. Res.704(1-3), 61-67 (2010).
4. Babiychuk, E.B., Atanassoff, A.P., Monastyrskaya, K., et al.PLoS One6(8), 1-9 (2011).
5. Zeidan, Y.H. and Hannun, Y.A. J. Biol. Chem.282(15), 11549-11561 (2011).
6. Sridevi, P., Alexander, H., Laviad, E.L., et al.Exp. Cell Res.316(1), 1-23 (2010).
7. Bionda, C., Hadchity, E., Alphonse, G., et al.Free Radic. Biol. Med.43(5), 681-694 (2007).
8. Verheij, M., Bose, R., Lin, H.L., et al.Nature380(6569), 75-79 (1996).
9. Zundel, W. and Giacca, A. Genes Dev.12(13), 1941-1946 (1998).
10. Hait, N.C., Allegood, J., Maceyka, M., et al.Science325, 1254-1257 (2009).
11. Rivera, J., Proia, R.L., and Olivera, A. Nat. Rev. Immunol.8, 753-763 (2008).
12. Shida, D., Takabe, K., Kapitonov, D., et al.Curr. Drug Targets9(8), 662-673 (2008).
13. Morita, Y., Perez, G.I., Paris, F., et al.Nat. Med.6(10),v 1109-1114 (2000).
14. Paris, F., Perez, G.I., Fuks, Z., et al.Nat. Med.8(9), 901-902 (2002).
15. Otala, M., Suomalainen, L., Pentikäinen, M.O., et al.Biol. Reprod.70, 759-767 (2004).
16. Bonnaud, S., Niaudet, C., Pottier, G., et al.Cancer Res.67(4), 1803-1811 (2007).
17. Mathew, B., Jacobson, J.R., Berdyshev, E., et al.FASEB J.25, 1-13 (2011).
The role of sphingolipid metabolic pathway has been recognized in determining cellular fate. Although sphingolipid degradation has been extensively studied, gene expression of human sphingosine 1-phosphate lyase (SPL) catalyzing sphingosine 1-phosphate (S1P) remains to be determined. Among 5 human lung cancer cell lines examined, SPL protein levels paralleled the respective mRNA and enzyme activities. Between H1155 and H1299 cells used for further experiments, higher cellular S1P was observed in H1155 with higher SPL activity compared with H1299 with low SPL activity. GATA-4 has been reported to affect SPL transcription in Dictyostelium discoideum. GATA-4 was observed in H1155 but not in other cell lines. Overexpression of GATA-4 in H1299 increased SPL expression. However, promoter analysis of human SPL revealed that the most important region was located between -136bp and -88bp from the first exon, where 2 Sp1 sites exist but no GATA site. DNA pull-down assay of H1155 showed increased DNA binding of Sp1 and GATA-4 within this promoter region compared with H1299. Electrophoresis mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assay, reporter assay using mutated binding motif, and mithramycin A, a specific Sp1 inhibitor, suggest the major role of Sp1 in SPL transcription and no direct binding of GATA-4 with this 5' promoter region. The collaborative role of GATA-4 was proved by showing coimmunoprecipitation of Sp1 and GATA-4 using GST-Sp1 and overexpressed GATA-4. Thus, high SPL transcription of H1155 cells was regulated by Sp1 and GATA-4/Sp1 complex formation, both of which bind to Sp1 sites of the 5'-SPL promoter.
Copyright © 2010 Elsevier B.V. All rights reserved.
Glucocerebrosidases (GBA) catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol.
β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide(Cer). Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro β-GlcChol is a member of sterylglycosides present in diverse species.
How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown.
Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol.
Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation.
Liquid chromatography-tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination.
We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes.
In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.
GBA1 (1q22) Lysosomaalinen glykosyylikeramidaasi, Glukokerebrosidaasi
https://www.genecards.org/cgi-bin/carddisp.pl?gene=GBA1&keywords=GBA1
GBA2 (9p13.3) Non-lysosomaalinen glykosyylikeramidaasi
https://www.genecards.org/cgi-bin/carddisp.pl?gene=GBA2&keywords=GBA2
GBA3 (4p15.2), Sytosolinen glukosyylikeramidaasi beeta 3 pystyy käsittelemään dietäärisiä glykosyyliyhdisteitäkin.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=GBA3&keywords=GBA3
The protein encoded by this gene is a cytosolic enzyme that can hydrolyze several types of glycosides. The enzyme has its highest activity at neutral pH and is predominantly expressed in human liver, kidney, intestine, and spleen. This gene is a polymorphic pseudogene, with the most common allele being the functional allele that encodes the full-length protein. Some individuals contain a single nucleotide polymorphism that results in a premature stop codon in the coding region, and therefore this allele is pseudogenic due to the failure to produce a functional full-length protein. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2022]
GBA3 (Glucosylceramidase Beta 3 (Gene/Pseudogene)) is a Protein Coding gene. Diseases associated with GBA3 include Gaucher's Disease. Among its related pathways are Sphingolipid metabolism and Metabolism. Gene Ontology (GO) annotations related to this gene include hydrolase activity, hydrolyzing O-glycosyl compounds and beta-glucosidase activity. An important paralog of this gene is LCT.
Neutral cytosolic beta-glycosidase with a broad substrate specificity that could play a role in the catabolism of glycosylceramides (PubMed:11389701, 11784319, 20728381, 26724485, 17595169, 33361282). Has a significant glucosylceramidase activity in vitro (PubMed:26724485, 17595169). However, that activity is relatively low and its significance in vivo is not clear (PubMed:26724485, 17595169, 20728381). Hydrolyzes galactosylceramides/GalCers, glucosylsphingosines/GlcSphs and galactosylsphingosines/GalSphs (PubMed:17595169). However, the in vivo relevance of these activities is unclear (PubMed:17595169). It can also hydrolyze a broad variety of dietary glycosides including phytoestrogens, flavonols, flavones, flavanones and cyanogens in vitro and could therefore play a role in the metabolism of xenobiotics (PubMed:11784319). Possesses transxylosylase activity in vitro using xylosylated ceramides/XylCers (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) as xylosyl donors and cholesterol as acceptor (PubMed:33361282). Could also play a role in the catabolism of cytosolic sialyl free N-glycans (PubMed:26193330). ( GBA3_HUMAN,Q9H227 )
Glycosylases are a group of enzymes that includes glucosidases, mannosidases and heparanases. There are two glucosidase subtypes, both found in the gut. They hydrolyze terminal (1,4)alpha-glucosidic linkages and (1,6)beta-glucosidic linkages, liberating alpha-glucose and beta-glucose.
AIEMPI tekstini:
Synteesi KERAMIDISTA kohti glykosfingolipidejä.KERAMIDI (Cer) syntyy endoplasmisessa retikulumissa ja se kulkeutuu Golgin laitteeseen.. Keramidia purkautuu myös sfingolipidien kataboliasta ja käytetään uudestaan.
GlcCer, glucosylceramide, glukosyylikeramidi
GlcCer syntaasientsyymi lisää glukoosin beta-sidoksella keramidin OH- ryhmään 1- asemassa.Glukosyylikeramidiin tapahtuva jatkosyntetisoiminen tapahtuu sen jälkeen kun karakterisoimattoman flippaasi-entsyymin avulla on tapahtunut vaihde Golgin laitteen ontelon puolelle.
http://link.springer.com/chapter/10.1007%2F978-4-431-67877-9_1#page-1
GalCer, galactosylceramide, galaktosyylikeramidi muodostusta voi myös joskus tapahtua keramidista. Tämä tapahtuu endoplasmisen retikulumin ontelon puolella, vaikkakin galaktosyylikeramidien synteesitietä tapahtuu vain hyvin rajoitetusti.
http://link.springer.com/chapter/10.1007%2F978-4-431-67877-9_8#page-1
On uudempaa tietoa on GlcCer ja GalCer muodostumisesta aineenvaihdunnassa vuodelta 2020
https://www.jbc.org/article/S0021-9258(17)48548-6/fulltext
β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain.
We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes.
In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.
Homo sapiens has evolved on a diet rich in alpha-linolenic acid C18:3 n3 (short omega3) and long chain polyunsaturated fatty acids (LCP). We have, however, gradually changed our diet from about 10,000 years ago and accelerated this change from about 100 to 200 years ago. The many dietary changes, including lower intake of omega3-fatty acids, are related to 'typically Western' diseases. After a brief introduction in essential fatty acids (EFA), LCP and their functions, this contribution discusses our present low status of notably LCP omega3 in the context of our rapidly changing diet within an evolutionary short time frame. It then focuses on the consequences in pregnancy, lactation and neonatal nutrition, as illustrated by some recent data from our group. We discuss the concept of a 'relative' EFA/LCP deficiency in the fetus as the outcome of high transplacental glucose flux. This flux may in the fetus augment de novo synthesis of fatty acids, which not only dilutes transplacentally transported EFA/LCP, but also causes competition of de novo synthesized oleic acid ( C18:1n9) with linoleic acid for delta-6 desaturation. Such conditions were encountered by us in mothers with high body mass indices, diabetes mellitus and preeclampsia. The unifying factor might be compromised glucose homeostasis. In search of the milk arachidonic acid (AA, C20:4n6) and docosahexaenoic acid (DHA, C22:6n3) contents of our African ancestors, we investigated women in Tanzania with high intakes of freshwater fish as only animal lipid source. These women had milk AA and DHA contents that were well above present recommendations for infant formulae. Both studies stimulate rethinking of 'optimal homeostasis'. Subtle signs of dysbalanced maternal glucose homeostasis may be important and observations from current Western societies may not provide us with an adequate basis for dietary recommendations.
