Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice.
Elongation of very long chain fatty acids (ELOVL)5 is one of seven mammalian fatty acid condensing enzymes involved in microsomal fatty acid elongation. To determine the in vivo substrates and function of ELOVL5, we generated Elovl5(-/-) mice. Studies using liver microsomal protein from wild-type and knockout mice demonstrated that the elongation of gamma-linolenic (C18:3, n-6) to dihomo-gamma-linolenic (C20:3, n-6) and stearidonic (C18:4, n-3) to omega3-arachidonic acid (C20:4, n-3) required ELOVL5 activity. Tissues of Elovl5(-/-) mice accumulated the C18 substrates of ELOVL5 and the levels of the downstream products, arachidonic acid (C20:4, n-6) and docosahexaenoic acid (DHA, C22:6, n-3), were decreased. A consequence of decreased cellular arachidonic acid and DHA concentrations was the activation of sterol regulatory element-binding protein (SREBP)-1c and its target genes involved in fatty acid and triglyceride synthesis, which culminated in the development of hepatic steatosis in Elovl5(-/-) mice. The molecular and metabolic changes in fatty acid metabolism in Elovl5(-/-) mice were reversed by dietary supplementation with arachidonic acid and DHA. These studies demonstrate that reduced ELOVL5 activity leads to hepatic steatosis, and endogenously synthesized PUFAs are key regulators of SREBP-1c activation and fatty acid synthesis in livers of mice.
Moon
Young-Ah
YA
From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046.
Hammer
Robert E
RE
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046.
Horton
Jay D
JD
From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046; Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046. Electronic address: jay.horton@utsouthwestern.edu.
D000123:Acetyltransferases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D015342:DNA Probes; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D015342:DNA Probes; D005227:Fatty Acids; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases