ELOVL4 protein preferentially elongates 20:5n3 to very long chain PUFAs over 20:4n6 and 22:6n3

Yu, Man; Benham, Aaron; Logan, Sreemathi; Brush, Richard S.; Mandal, Nawajes A.; Anderson, Robert E.; Agbaga, Martin-Paul

doi:10.1194/jlr.m021386

Cited by 54 publications

(69 citation statements)

References 75 publications

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“…Both AA and DHA suppress SREBP and its target genes in FA triglyceride synthesis and development of hepatic steatosis (Moon et al, 2009). Elovl4 is expressed in retina, brain and testes and is involved in elongation steps required for DHA synthesis (Yu et al, 2012). Elovl5 induces changes in hepatic FA content and influences multiple pathways in lipid and carbohydrate metabolism and attenuates hyperglycemia in DIO mice and restores insulin sensitivity.…”

Section: Lipid Metabolism In Control Of Eicosanoid Synthesismentioning

confidence: 99%

Eicosanoids in Metabolic Syndrome

Hardwick

Eckman

Lee

et al. 2013

Advances in Pharmacology

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Chronic persistent inflammation plays a significant role in disease pathology of cancer, cardiovascular disease, and metabolic syndrome (MetS). MetS is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. Nonalcoholic fatty liver disease (NAFLD) is associated with many of the MetS diseases. These metabolic derangements trigger a persistent inflammatory cascade, which includes production of lipid autacoids (eicosanoids) that recruit immune cells to the site of injury and subsequent expression of cytokines and chemokines that amplify the inflammatory response. In acute inflammation, the transcellular synthesis of antiinflammatory eicosanoids resolve inflammation, while persistent activation of the autacoid-cytokine-chemokine cascade in metabolic disease leads to chronic inflammation and accompanying tissue pathology. Many drugs targeting the eicosanoid pathways have been shown to be effective in the treatment of MetS, suggesting a common linkage between inflammation, MetS and drug metabolism.The cross-talk between inflammation and MetS seems apparent because of the growing evidence linking immune cell activation and metabolic disorders such as insulin resistance, dyslipidemia, and hypertriglyceridemia. Thus modulation of lipid metabolism through either dietary adjustment or selective drugs may become a new paradigm in the treatment of metabolic disorders. This review focuses on the mechanisms linking eicosanoid metabolism to persistent inflammation and altered lipid and carbohydrate metabolism in MetS.

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Section: Lipid Metabolism In Control Of Eicosanoid Synthesismentioning

confidence: 99%

Eicosanoids in Metabolic Syndrome

Hardwick

Eckman

Lee

et al. 2013

Advances in Pharmacology

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“…Fatty acid methyl esters (FAMES) were generated, extracted, and analyzed by GC-MS as described by Agbaga et al (9). Fatty acid molar values and relative mole percents were directly measured by GC-flame ionization detector using 15:0, 17:0, and 30:3n6 internal standards as described by Yu et al (49).…”

Section: Methodsmentioning

confidence: 99%

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.Stargardt disease | condensing enzyme | photoreceptor degeneration

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“…Data are limited to AA, DHA, and fatty acid species involved in the ELOVL4-mediated elongation pathway. 8 At 1 month of age, the concentration of LC-and VLC-PUFA in WT and TG do not differ significantly. In WT, AA and DHA are continuously increased until 18 months and then drastically decrease at 24 months.…”

Section: Retinal Profile Of Fatty Acids In Tg Micementioning

confidence: 94%

“…This widely conserved gene encodes a very long-chain fatty acid elongase. [6][7][8] All of these mutations induce a truncation of the wild-type (WT) ELOVL4 protein at its C-terminus, and the subsequent deletion of a dilysine motif necessary for retention of transmembrane proteins in the endoplasmic reticulum (ER). Although recently challenged, 9 cellular mislocation of the truncated ELOVL4 protein to perinuclear aggresomes 10,11 and altered synthesis of very long-chain polyunsaturated fatty acids (VLC-PUFA) are currently considered to be at the origin of the disease.…”

mentioning

confidence: 99%