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Incorporation of Chylomicron Fatty Acids Into the Developing Rat Brain

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Incorporation of Chylomicron Fatty Acids Into the Developing Rat Brain Incorporation of chylomicron fatty acids into the developing rat brain. G J Anderson, … , P S Tso, W E Connor J Clin Invest. 1994;93(6):2764-2767. https://doi.org/10.1172/JCI117293. Research Article The developing brain obtains polyunsaturated fatty acids from the circulation, but the mechanism and route of delivery of these fatty acids are undetermined. 14C-labeled chylomicrons were prepared by duodenal infusion of [1-14C]16:0, [1- 14C]18:2(n-6), [1-14C]18:3(n-3), or [1-14C]22:6(n-3) into adult donor rats, and were individually injected into hepatectomized 2-wk-old suckling rats. After minor correction for trapped blood in the brain, the incorporation of chylomicron fatty acids after 30 min was nearly half that of a co-injected free fatty acid reference. [1-14C]22:6(n-3)-labeled chylomicrons showed an average 65% greater incorporation than chylomicrons prepared from the other fatty acids. This apparent selectivity may have been partly due to lower oxidation of 22:6(n-3) in the brain compared to the other fatty acids tested, based on recovered water-soluble oxidation products. The bulk of the radioactivity in the brain was found in phospholipid and triacylglycerol, except that animals injected with [1-14C]22:6(n-3) chylomicrons showed considerable incorporation also into the fatty acid fraction instead of triacylglycerol. These data show that chylomicrons may be an important source of fatty acids for the developing rat brain. Find the latest version: https://jci.me/117293/pdf Rapid Publication Incorporation of Chylomicron Fatty Acids into the Developing Rat Brain Gregory J. Anderson,* Patrick S. Tso,* and William E. Connor* 'Section of Clinical Nutrition and Lipid Metabolism, Oregon Health Sciences University, Portland, Oregon 97201; and tDepartment of Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130 Abstract acids are being actively laid down (10). We present data here on the incorporation of chylomicron-bound 22:6(n-3) and The developing brain obtains polyunsaturated fatty acids from other fatty acids into the developing rat brain. the circulation, but the mechanism and route of delivery of these fatty acids are undetermined. '4C-labeled chylomicrons Methods were prepared by duodenal infusion of I1-'4C116:0, 11- '4C118:2(n-6), I1-'4C118:3(n-3), or I1-14C122:6(n-3) into Isotopes were purchased from New England Nuclear Research Prod- adult donor rats, and were individually injected into hepatecto- ucts (Boston, MA); [9,10-3H1 18:1 (n-9) was purified by silica gel thin mized 2-wk-old suckling rats. After minor correction for layer chromatography before use. Sprague-Dawley rat litters were pur- trapped blood in the brain, the incorporation of chylomicron chased from Simonsen (Gilroy, CA) and were allowed at least one day fatty acids after 30 min was nearly half that of a coinjected free to recover from any stress associated with shipment. Only 13-15-d-old fatty acid reference. 11-14C122:6(n-3)-labeled chylomicrons male pups were used in the experiments. showed an average 65% greater incorporation than chylomi- Chylomicrons were prepared in lymph-fistula rats as described crons prepared from the other fatty acids. This apparent selec- (14). Adult donor rats were fitted with cannulae in the duodenum and the mesenteric lymph duct. 50-100 gCi of a 1- '4C-fatty acid ( 16:0, tivity may have been partly due to lower oxidation of 22:6(n-3) 18:2[n-61, 18:3[n-3], or 22:6[n-3]; 40-60 mCi/mmol) was emulsi- in the brain compared to the other fatty acids tested, based on fied into 3 ml ofa lipid emulsion containing phosphate-buffered saline, recovered water-soluble oxidation products. The bulk of the pH 6.4, 40 umol triolein, 8.8 Mmol egg lecithin, and 57 ,umol sodium radioactivity in the brain was found in phospholipid and tria- taurocholate. The labeled emulsion was infused into the duodenum cylglycerol, except that animals injected with 1-14C122:6(n-3) over a 30-min period, followed by steady infusion of the nonradioac- chylomicrons showed considerable incorporation also into the tive lipid emulsion at 3 ml/h. Lymph was collected for 4 h, with most fatty acid fraction instead of triacylglycerol. These data show of the radioactivity recovered in the first 3 h. Recovery of radioactivity that chylomicrons may be an important source of fatty acids for in the lymph ranged from - 30% (for [1-'4C] 16:0) to 50-60% ([1- the developing rat brain. (J. Clin. Invest. 1994. 93:2764-2767.) 14C]18:2[n-6], [I-'4C]18:3[n-3], and [1-'4C]22:6[n-3]). Chylomi- * crons were isolated by ultracentrifugation (15) with 85% recovery of Key words: brain * chylomicrons * docosahexaenoic acid pal- lymph radioactivity. The purity of the preparation was estimated by mitic acid * linoleic acid * linolenic acid * rat recentrifugation of an aliquot of VLDL (from control rat lymph) under the above conditions designed for isolation of chylomicrons. Introduction Only 3-5% of the VLDL was recovered in the traditional chylomicron fraction. Since VLDL is a comparatively minor component of intes- Long-chain polyunsaturated fatty acids are processed into the tinal lymph, this indicates that VLDL contamination of the original developing rat brain principally during the first 3 wk ofpostna- chylomicron preparation was negligible. Chylomicron fractions were tal life ( 1, 2). Docosahexaenoic acid (22:6 [n-3 ]) is the most assayed for triacylglycerol content on an Abbott VP Chemistry Ana- prevalent n-3 polyunsaturated fatty acid found in the brain (for lyzer (Abbott Laboratories, Abbott Park, IL). The specific activity of review see reference 3), and its uptake and incorporation into the chylomicrons ranged between 0.3-0.4 ,Ci/mg triacylglycerol. the brain has been examined However, it is still not To further characterize the chylomicrons, aliquots were extracted (4-8). by the method of Folch et al. ( 16) and subjected to silica gel TLC with clear how 22:6(n-3) reaches the brain. One potential delivery hexane:chloroform:ether:acetic acid (80:10:10:1.5). Triacylglycerol route for fatty acids, via chylomicrons, has only been examined represented 86-96% of the lipid radioactivity, with small amounts of in adult rats (9). In that study it was found that very little phospholipid (2-8%), cholesterol ( 1-4%), fatty acid ( 1-5%), and cho- radioactivity from [ 1- '2C ] 16:0-labeled chylomicronswas incor- lesteryl ester (0-0.5%). '4C-labeled water-soluble oxidation products porated into the brain. constituted 0.03-1.32% of total chylomicron radioactivity. Before in- Lipoprotein lipase, the endothelial enzyme responsible for jection, the chylomicron preparations were complexed with [9,10- hydrolyzing triacylglycerol in chylomicrons and VLDL, is pres- 3H] 18:1 (n-9) to compare incorporation of chylomicron fatty acids ent in the brain ( 10-13 ), and in fact peaks during the period of with that of a free fatty acid. Since results from 14C- and 3H-labeled postnatal development in the rat when polyunsaturated fatty compounds are not necessarily strictly comparable, the incorporation of [3H] 18:1 cannot be compared directly with individual '4C-labeled fatty acids. Thus, incorporation data for [3H] 18:1 in the form of free Address correspondence to Gregory J. Anderson, Department of Medi- fatty acid are included only to put the incorporation of chylomicron cine L465, Oregon Health Sciences University, Portland, OR 97201. fatty acids into perspective, since free fatty acids are the "presumed" Receivedfor publication 9 December 1992 and in revisedform 20 vehicle for fatty acid delivery to the brain ( 17). The [9,10-3H] 18:1 (n- December 1993. 9) was dried under nitrogen, a sample of the chylomicron preparation added, and the solution mixed gently with magnetic stirring for 15 min J. Clin. Invest. at room temperature. TLC ofa lipid extract ofthe [3H] 18:1 complexed © The American Society for Clinical Investigation, Inc. chylomicrons showed that > 98% of the tritium was recovered as fatty 0021-9738/94/06/2764/04 $2.00 acid. An aliquot of [ 3H ] 18:1 complexed chylomicrons was subjected to Volume 93, June 1994, 2764-2767 ultracentrifugation as above. The majority of the tritium label, 62%, 2764 Anderson, Tso, and Connor Table I. Incorporation ofFatty Acids into the 2-wk-old Developing Rat Brain After Intravenous Injection of"C-Chylomicrons and 3H-Free Fatty Acid 4C-chylomicrons* 3H-FFA 16:0 18:2 18:3 22:6 18:1 Brain weight (g) 1.02±0.06 1.08±0.05 1.03±0.02 0.99±0.04 1.03±0.05 Radioactivity (DPM)t 4790±860 4550±810 5120±1230 7590±1640 12630±2720 Incorporation1 (102 x [% dose/g]) 10.6±2.1a 9.4+1.5a 11.2±2.6a 17.2±3.4b 27.8±6.4 n 7 4 4 5 19 * The indicated '4C-labeled fatty acids were infused with tnolein into adult donor rats and the mesenteric lymph collected (see Methods). For free fatty acids (FFA), [3H]18:1(n-9) was complexed with each chylomicron preparation. Data are means±SD. Normalized to a dose of 2 lCi. § Values with unlike superscripts are different at P = 0.003. was present in the infranatant fraction (presumably associated with 14C] 18:2(n-6), or [1-24C] 18:3(n-3). The average incorpora- fatty acid binding protein[s], such as albumin) while the rest, 38%, was tion of 1- 14C-labeled chylomicron fatty acids, expressed as a present in the chylomicron fraction. percentage of injected dose, was almost half that of unesterified Rat pups were anesthetized with ketamine/xylazine/aceproma- 3H] 18:1 (n-9), which was coinjected with the chylomicrons.
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