Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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 γ-linolenic (C18:3, n-6) to dihomo-γ-linolenic (C20:3, n-6) and stearidonic (C18:4, n-3) to ω3-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.

Original languageEnglish (US)
Pages (from-to)412-423
Number of pages12
JournalJournal of Lipid Research
Volume50
Issue number3
DOIs
StatePublished - Apr 2009

Fingerprint

Sterol Regulatory Element Binding Protein 1
Fatty Liver
Liver
Fatty Acids
Chemical activation
Arachidonic Acid
Elongation
Docosahexaenoic Acids
Substrates
Dietary Supplements
Metabolism
Knockout Mice
Triglycerides
Genes
Tissue
Enzymes

Keywords

  • Elongation of very long chain fatty acids
  • Fatty acid synthesis
  • Hepatic steatosis
  • PUFAs
  • Sterol regulatory element-binding protein

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. / Moon, Young Ah; Hammer, Robert E; Horton, Jay D.

In: Journal of Lipid Research, Vol. 50, No. 3, 04.2009, p. 412-423.

Research output: Contribution to journalArticle

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N2 - 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 γ-linolenic (C18:3, n-6) to dihomo-γ-linolenic (C20:3, n-6) and stearidonic (C18:4, n-3) to ω3-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.

AB - 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 γ-linolenic (C18:3, n-6) to dihomo-γ-linolenic (C20:3, n-6) and stearidonic (C18:4, n-3) to ω3-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.

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