Advertisement

Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and α-linolenate

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Recent reports indicate that recycling of the β-oxidized carbon skeleton of linoleate and α-linolenate into newly synthesized cholesterol and fatty acids in the brain is quantitatively significant in both suckling rats and pre- and postnatally in rhesus monkeys. The recycling appears to occur via ketones which are not only readily produced from these 18 carbon polyunsaturates but are also the main lipogenic precursors for the developing mammalian brain. Since the neonatal rat brain appears not to acquire cholesterol or long chain saturated or monounsaturated fatty acids from the circulation, ketones and ketogenic precursors seem to be crucial for normal brain synthesis of these lipids. Cholesterol is plentiful in brain membranes and it has also been discovered to be the essential lipid adduct of the ‘hedgehog’ family of proteins, the appropriate expression of which determines normal embryonic tissue patterning and neurological development. Insufficient cholesterol or inappropriate expression of ‘sonic hedgehog’ has major adverse neurodevelopmental consequences typified in humans by Smith-Lemli-Optiz syndrome. Hence, we propose that the importance of α-linolenate and linoleate for normal neural development arises not only from being precursors to longer chain polyunsaturates incorporated into neuronal membranes but, perhaps equally importantly, by being ketogenic precursors needed for in situ brain lipid synthesis.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Prostaglandins, Leukotrienes and Essential Fatty Acids
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Crawford M.A.
        The role of dietary fatty acids in biology: their place in the evolution of the human brain.
        Nutr Rev. 1992; 50: 3-11
        • Bourre J.M.
        • Pascal G.
        • Durand G.
        • Masson M.
        • Dumont O.
        • Picotti M.
        Alterations in the fatty acid composition of rat brain cells (neurons, astrocytes, and oligodendrocytes) and of subcellular fractions (myelin, synaptosomes) induce by a diet devoid of n-3 fatty acids.
        J Neurochem. 1984; 43: 342-348
        • Neuringer M.
        • Connor W.E.
        • Lin D.S.
        • Barstad L.
        • Luck S.
        Biochemical and functional effects of prenatal and postnatal omega-3 fatty acid deficiency on retina and brain in rhesus monkeys.
        in: Proc Natl Acad Sci USA. 83. 1986: 4021-4025
        • Palowsky R.J.
        • Ward G.
        • Salem Jr., N.
        Essential fatty acid uptake and metabolism in the developing rodent brain.
        Lipids. 1996; 31: S103-S107
        • Carnielli V.P.
        • Wattimena D.J.
        • Luijendijk I.H.
        • Boerlage A.
        • Degenhart H.J.
        • Sauer P.J.J.
        The very low birth weight premature infant is capable of synthesized arachidonic and docosahexaenoic acids from linoleic and linoleinic acids.
        Pediatr Res. 1996; 40: 169-174
        • Agostoni C.
        • Trojan S.
        • Bellu R.
        • Riva E.
        • Giovannini M.
        Neurodevelopmental quotient of healthy term infants at 4 months and feeding practice: the role of long chain polyunsaturated fatty acids.
        Pediatr Res. 1995; 38: 262-266
        • Makrides M.
        • Neumann M.
        • Simmer K.
        • Pater J.
        • Gibson R.
        Are long chain fatty acids essential nutrients in infancy?.
        Lancet. 1995; 345: 1463-1468
      1. Anderson G.J., Connor W.E., Corliss J.D. Docosahexaenoic acid is the preferred dietary n-3 fatty acid for the development of the brain and retina. Pediatr Res 27: 89–97.

        • Cunnane S.C.
        The Canadian Society for Nutritional Sciences 1995 Young Scientist Award Lecture.
        Can J Physiol Pharmacol. 1996; 74: 629-639
        • Farquharson J.
        • Cockburn F.
        • Patrick W.A.
        • Jamieson E.C.
        • Logan R.W.
        Infant cerebral cortex phospholipid fatty acid composition and diet.
        Lancet. 1992; 340: 810-813
        • Chen Z.-Y.
        • Cunnane S.C.
        Refeeding after fasting increases apparent oxidation of n-6 and n-3 fatty acids in pregnant rats.
        Metabolism. 1993; 42: 1206-1211
        • Cunnane S.C.
        • Yang J.
        Zinc deficiency impairs whole body accumulation of polyunsaturates and increases the utilization of [1-14C]-linoleate for de novo lipid synthesis in pregnant rats.
        Can J Physiol Pharmacol. 1995; 73: 1246-1252
        • Cunnane S.C.
        • Williams S.C.R.
        • Bell J.D.
        • et al.
        Utilization of [U-13C] polyunsaturated fatty acids in the synthesis of cholesterol and long chain fatty acids in the developing rat brain.
        J Neurochem. 1994; 62: 2429-2436
        • Likhodii S.S.
        • Cunnane S.C.
        Utilization of carbon from dietary polyunsaturates for brain cholesterol synthesis during early postnatal development in the rat: a 13C NMR study.
        Magn Reson Med. 1995; 34: 803-813
        • Sheaff-Greiner R.C.
        • Zhang Q.
        • Goodman K.J.
        • Giussani D.A.
        • Nathanielsz P.W.
        • Brenna J.T.
        Linoleate, α-linolenate and docosahexaenoate recycling into saturated and monounsaturated fatty acids is a major pathway in pregnant or lactating adults and fetal or infant rhesus monkeys.
        J Lipid Res. 1996; 37: 2675-2686
        • Menard C.R.
        • Goodman K.J.
        • Corso T.N.
        • Brenna J.T.
        • Cunnane S.C.
        Recycling of carbon into lipids synthesized de novo is a quantitatively important pathway of [U-13C]-α-linolenate utilization in the developing rat brain.
        J Neurochem. 1998; 71: 2151-2158
        • Dhopeswarkar G.A.
        • Subramanian C.
        Metabolism of linolenic acid in the developing brain. 1. Incorporation of radioactivity from [1-14C]-linolenic acid into brain fatty acids.
        Lipids. 1975; 10: 238-241
        • Sinclair A.J.
        Incorporation of radioactive polyunsaturated fatty acids into liver and brain of the developing rat.
        Lipids. 1975; 10: 175-184
        • Cunnane S.C.
        • Anderson M.J.
        Pure linoleate deficiency in the rat: influence on growth, accumulation of n-6 polyunsaturates and oxidation of 14C-linoleate.
        J Lipid Res. 1997; 38: 805-812
        • Cunnane S.C.
        • Belza K.
        • Anderson M.J.
        • Ryan M.A.
        Substantial carbon recycling from linoleate into products of de novo lipogenesis occurs in rat liver even under conditions of extreme linoleate deficiency.
        J Lipid Res. 1998; 39: 2271-2276
        • Cuzner M.L.
        • Davison A.N.
        The lipid composition of rat brain myelin and subcellular fractions during development.
        Biochem J. 1968; 106: 29-34
        • Porter J.A.
        • Young K.E.
        • Beachy P.A.
        Cholesterol modification of Hedgehog signaling proteins in animal development.
        Science. 1996; 274: 255-259
        • Chiang C.
        • Litingtung Y.
        • Lee E.
        • et al.
        Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
        Nature. 1996; 383: 407-413
        • Tint G.S.
        • Irons M.
        • Elias E.R.
        • et al.
        Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome.
        New Engl J Med. 1994; 330: 107-113
        • Salen G.
        • Shefer S.
        • Batta A.K.
        • et al.
        Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome.
        J Lipid Res. 1996; 37: 1169-1180
        • Edmond J.
        • Higa T.A.
        • Korsak R.A.
        • Bergner E.A.
        • Lee W.N.P.
        Fatty acid transport and utilization for the developing brain.
        J Neurochem. 1998; 70: 1227-1234
        • Edmond J.
        • Korsak R.A.
        • Morrow J.W.
        • Torok-Booth G.
        • Catlin D.H.
        Dietary cholesterol and the origin of cholesterol in the brain of developing rats.
        J Nutr. 1991; 121: 1323-1330
        • Jurevics H.
        • Morell P.
        Cholesterol for synthesis of myelin is made locally, not imported into the brain.
        J Neurochem. 1995; 64: 895-901
        • Zhang S.
        • Wong W.W.
        • Hachey D.L.
        • Pond W.G.
        • Klein P.D.
        Dietary cholesterol inhibits whole-body but not cerebrum cholesterol synthesis in young pigs.
        J Nutr. 1994; 124: 717-725
        • Belknap W.M.
        • Dietschy J.M.
        Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta and fetus.
        J Clin Invest. 1988; 82: 2077-2085
        • Hawkins R.A.
        • Williamson D.H.
        • Krebs H.A.
        Ketone-body utilization by adult and suckling rat brain in vivo.
        Biochem J. 1971; 122: 13-18
        • Cremer J.E.
        Substrate utilization and brain development.
        J Cerebral Blood Flow and Metab. 1982; 2: 394-407
        • Page M.A.
        • Krebs H.A.
        • Williamson D.H.
        Activities of enzymes of ketone-body utilization in brain and other tissues of suckling rats.
        Biochem J. 1971; 121: 34-49
        • Robinson A.M.
        • Williamson D.H.
        Physiological roles of ketone bodies as substrates and signals in mammalian tissues.
        Physiol Rev. 1980; 60: 143-187
        • Yeh Y.-Y.
        • Streuli V.L.
        • Zee P.
        Ketone bodies serve as important precursors of brain lipids in the developing rat.
        Lipids. 1977; 12: 957-964
        • Edmond J.
        Ketone bodies as precursors of sterols and fatty acids in the developing rat.
        J Biol Chem. 1974; 249: 72-80
        • Patel M.S.
        • Owen O.E.
        Development and regulation of lipid synthesis from ketone bodies by rat brain.
        J Neurochem. 1977; 28: 109-114
        • Webber R.J.
        • Edmond J.
        The in vivo utilization of acetoacetate, D(−)-3-hydroxybutyrate and glucose for lipid synthesis in the brain of the 18-day old rat: evidence for an acetyl-CoA bypass for sterol synthesis.
        J Biol Chem. 1979; 254: 3912-3920
        • Bekesi A.
        • Williamson D.H.
        An explanation for ketogenesis by the intestine of the suckling rat: the presence of an active hydroxymethylglutaryl-Coenzyme A pathway.
        Biol Neonate. 1990; 58: 160-165
        • Bjorntorp J.
        Rates of oxidation of different fatty acids by isolated rat liver mitochondria.
        J Biol Chem. 1968; 243: 2130-2133
        • Leyton J.
        • Drury P.J.
        • Crawford M.A.
        Differential oxidation of saturated and unsaturated fatty acids in vivo in the rat.
        Br J Nutr. 1987; 57: 383-393
        • Gavino G.R.
        • Gavino V.C.
        Rat liver mitochondrial carnitine palmitoyl transferase activity towards long chain polyunsaturated fatty acids and their CoA esters.
        Lipids. 1991; 26: 266-271
        • Jones P.J.H.
        • Pencharz P.B.
        • Clandinin M.T.
        Whole body oxidation of dietary fatty acids: Implications for energy utilization.
        Am J Clin Nutr. 1985; 42: 769-777
        • Jones P.J.H.
        • Scholler D.A.
        Polyunsaturated: saturated ratio of diet fat influences energy substrate utilization in the human.
        Metabolism. 1988; 37: 145-151
        • Jones P.J.H.
        Dietary linoleic, α-linolenic and oleic acids are oxidized at similar rates in rats fed a diet containing these acids in equal proportions.
        Lipids. 1994; 29: 491-495
        • Emmison N.
        • Gallagher P.A.
        • Coleman R.A.
        Linoleic and α-linolenic acids are selectively secreted in triacylglycerol by hepatocytes from neonatal rats.
        Am J Physiol. 1995; 269: R80-R86
        • Holliday M.A.
        Metabolic rate and organ size during growth from infancy to maturity and during late gestation and early infancy.
        Pediatrics. 1971; 47: 169-179
        • Selivonchick D.P.
        • Johnson P.V.
        Fat deficiency in rats during development of the central nervous system and susceptibility to experimental allergic encephalomyelitis.
        J Nutr. 1975; 105: 288-300
        • Greiner R.C.S.
        • Winter J.
        • Nathanielsz P.W.
        • Brenna J.T.
        Brain docosahexaenoate in fetal baboons: Bioequivalence of dietary α-linolenic and docosahexaenoic acids.
        Pediatr Res. 1997; 42: 826-834
        • Crawford M.A.
        • Hassam A.G.
        • Williams G.
        • Whitehouse W.
        Fetal accumulation of long chain polyunsaturated fatty acids.
        Adv Exper Biol Med. 1977; 83: 135-143
        • Cenedella R.J.
        • Allen A
        Differences between the metabolism of linoleic and palmitic acid: utilization for cholesterol synthesis and oxidation to respiratory CO2.
        Lipids. 1969; 4: 155-158
        • Dupont J.
        Fatty acid oxidation in relation to cholesterol biosynthesis in rats.
        Lipids. 1966; 6: 415-421