Upregulated liver conversion of a-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet

We quantified incorporation rates of plasmaderived a-linolenic acid (a-LNA, 18:3n-3) into “stable” liver lipids and the conversion rate of a-LNA to docosahexaenoic acid (DHA, 22:6n-3) in male rats fed, after weaning, an n-3 PUFA-adequate diet (4.6% a-LNA, no DHA) or an n-3 PUFAdeficient diet (0.2% a-LNA, no DHA) for 15 weeks. Unanesthetized rats were infused intravenously with [1-C]a-LNA, and arterial plasma was sampled until the liver was microwaved at 5min. Unlabeleda-LNA andDHA concentrations in arterial plasma and liver were reduced.90% by deprivation, whereas unlabeled arachidonic acid (20:4n-6) and docosapentaenoic acid (22:5n-6) concentrations were increased. Deprivation did not changea-LNA incorporation coefficients into stable liver lipids but increased synthesis-incorporation coefficients of DHA from a-LNA by 6.6-, 8.4-, and 2.3-fold in triacylglycerol, phospholipid, and cholesteryl ester, repectively. Assuming that synthesized-incorporated DHA even tually would be secreted within lipoproteins, calculated liver DHA secretion rates equaled 2.19 and 0.82 mmol/day in the n-3 PUFA-adequate and -deprived rats, respectively. These rates exceed the published rates of brain DHA consumption by 6and 10-fold, respectively, and should be sufficient to maintain normal and reduced brain DHA concentrations, respectively, in the two dietary conditions.— Igarashi, M., J. C. DeMar, Jr., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. Upregulated liver conversion of a-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet. J. Lipid Res. 2007. 48: 152–164. Supplementary key words deprivation & incorporation & turnover & synthesis & pulse labeling & diet & brain & polyunsaturated fatty acid a-Linolenic acid (a-LNA, 18:3n-3) is a nutritionally essential PUFA that must be obtained through the diet. It can be converted in vertebrate tissue to docosahexaenoic acid (DHA, 22:6n-3) through serial steps of desaturation and elongation with final peroxisomal chain shortening (1), by means of desaturases and elongases (2–5). Controversy exists regarding the extent of DHA synthesis from a-LNA in brain and liver. In immature rats, Scott and Bazan (6) suggested that the brain does not synthesize enough DHA to maintain its DHA composition but must receive the DHA that has been converted from a-LNA by the liver to do so. To address issues such as this, we recently developed pulse-labeling methods involving the intravenous infusion of [1-C]a-LNA to estimate conversion rates of plasma a-LNA to DHA in brain and liver of unanesthetized rats and showed that each of these organs converted ,1% of their plasma-derived unesterified aLNA to DHA (7, 8). However, on a per gram basis, in rats fed a high-DHA diet (2.3% of total fatty acids), conversion rates of plasma a-LNA to DHA were 0.24 and 6.6 nmol/s/g tissue 3 10 in brain and liver, respectively (7, 9, 10). Thus, the liver has a 27.5-fold greater conversion rate per gram than does brain in such rats. In this study, we examined the effect of altering dietary n-3 PUFA composition on liver composition and conversion rates of a-LNA to DHA in unanesthetized rats. Based on evidence that high amounts of dietary DHA or a-LNA suppress the expression in rat liver of D5 and D6 desaturases and elongases that catalyze DHA synthesis froma-LNA (1–4, 11) and that DHA synthesis from a-LNA is reduced in rat astrocytes incubated with DHA (12), we hypothesized that conversion would be upregulated in rats fed a diet with low compared with adequate n-3 PUFA content. Manuscript received 5 September 2006 and in revised form 17 October 2006. Published, JLR Papers in Press, October 18, 2006. DOI 10.1194/jlr.M600396-JLR200 Abbreviations: AA, arachidonic acid (20:4n-6); DHA, docosahexaenoic acid (22:6n-3); DPA, docosapentaenoic acid (22:5); EPA, eicosapentaenoic acid (20:5n-3); FAME, fatty acid methyl ester; LA, linoleic acid (18:2n-6); a-LNA, a-linolenic acid (18:3n-3); UV, ultraviolet. 1 To whom correspondence should be addressed. e-mail: [email protected] 2 Present address of J. C. DeMar, Jr.: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892. The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three tables. This article is available online at http://www.jlr.org 152 Journal of Lipid Research Volume 48, 2007 by gest, on S etem er 8, 2017 w w w .j.org D ow nladed fom 0.DC1.html http://www.jlr.org/content/suppl/2006/10/25/M600396-JLR20 Supplemental Material can be found at: