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Originally published In Press as doi:10.1194/jlr.M800123-JLR200 on March 30, 2008

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Journal of Lipid Research, Vol. 49, 1538-1552, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Elevated hepatic fatty acid elongase-5 activity affects multiple pathways controlling hepatic lipid and carbohydrate composition*,boxs

Yun Wang*, Moises Torres-Gonzalez{dagger}, Sasmita Tripathy{dagger}, Daniela Botolin*, Barbara Christian* and Donald B. Jump1,*,{dagger}

* Departments of Physiology, Biochemistry, and Molecular Biology, Michigan State University, East Lansing, MI 48824
{dagger} Department of Nutrition and Exercise Sciences, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331

* This project was supported by the National Institutes of Health (Grant DK-43220), the National Research Initiative of the U.S. Department of Agriculture Cooperative State Research, Education and Extension Service (2003-35200-13400), the Michigan Agriculture Experiment Station, and the College of Health and Human Sciences at Oregon State University.

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four figures.

Published, JLR Papers in Press, March 30, 2008.

1 To whom correspondence should be addressed. e-mail: jump{at}oregonstate.edu

Hepatic fatty acid elongase-5 (Elovl-5) plays an important role in long chain monounsaturated and polyunsaturated fatty acid synthesis. Elovl-5 activity is regulated during development, by diet, hormones, and drugs, and in chronic disease. This report examines the impact of elevated Elovl-5 activity on hepatic function. Adenovirus-mediated induction of Elovl5 activity in livers of C57BL/6 mice increased hepatic and plasma levels of dihomo-{gamma}-linolenic acid (20:3,n-6) while suppressing hepatic arachidonic acid (20:4,n-6) and docosahexaenoic acid (22:6,n-3) content. The fasting-refeeding response of peroxisome proliferator-activated receptor {alpha}-regulated genes was attenuated in mice with elevated Elovl5 activity. In contrast, the fasting-refeeding response of hepatic sterol-regulatory element binding protein-1 (SREBP-1)-regulated and carbohydrate-regulatory element binding protein/Max-like factor X-regulated genes, Akt and glycogen synthase kinase (Gsk)-3β phosphorylation, and the accumulation of hepatic glycogen content and nuclear SREBP-1 were not impaired by elevated Elovl5 activity. Hepatic triglyceride content and the phosphorylation of AMP-activated kinase {alpha} and Jun kinase 1/2 were reduced by elevated Elovl5 activity. Hepatic phosphoenolpyruvate carboxykinase expression was suppressed, while hepatic glycogen content and phosphorylated Gsk-3β were significantly increased, in livers of fasted mice with increased Elovl5 activity. As such, hepatic Elovl5 activity may affect hepatic glucose production during fasting. In summary, Elovl5-induced changes in hepatic fatty acid content affect multiple pathways regulating hepatic lipid and carbohydrate composition.

Supplementary key words fatty acid synthesis • gene transcription • PPAR{alpha}

Abbreviations: ACS, acyl-CoA synthetase; AMPK, AMP-activated kinase; ChREBP, carbohydrate-regulatory element binding protein; CTE1, cytosolic fatty acid thioesterase-1; CYP4A, cytochrome P450 4A; Elovl, fatty acid elongase; Erk, extracellular receptor kinase; Gsk-3β, glycogen synthase kinase-3β; HNF-4{alpha}, hepatic nuclear factor-4{alpha}; JNK, Jun kinase; L-PK, L-type (liver) pyruvate kinase; LXR, liver X receptor; MLX, Max-like factor X; mtHMG-CoA synthase, mitochondrial hydroxymethylglutaryl-CoA synthase; PepCk, phosphoenolpyruvate carboxykinase; PPAR{alpha}, peroxisome proliferator-activated receptor {alpha}; RP, reverse-phase; SCD1, stearoyl-CoA desaturase; SREBP, sterol-regulatory element binding protein


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