Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice

Tripathy, Sasmita; Lytle, Kelli A.; Stevens, Robert; Bain, James R.; Newgard, Christopher B.; Greenberg, Andrew S.; Huang, Li‐Shin; Jump, Donald Β.

doi:10.1194/jlr.m050062

Cited by 48 publications

(43 citation statements)

References 65 publications

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“…The largest response of this group involves the synergistic suppression of Scd1, which diverts fatty acids from oxidation to storage as triglycerides [16–17]. Malic enzyme 1 (Me1), acetyl-CoA carboxylase beta (Acacb), pyruvate dehydrogenase kinase 4 (Pdk4) and elongation of very long chain fatty acids protein 5 (Elovl5) are additional genes, which exhibit pivotal roles in stimulating fatty acid synthesis, that also decline selectively on the HFD [59–62]. The serum regulators of liver metabolism, insulin-like growth factor binding protein 1 (Igfbp1), which decreases IGF1 bioavailability, and fibroblast growth factor 21 (Fgf21), another important regulator of fatty acid metabolism [63–64], each demonstrated paralleled suppression with HFD and Cyp1b1 deletion.…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Larsen

Bushkofsky

Gorman

et al. 2015

Archives of Biochemistry and Biophysics

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Cytochrome P450 1b1 (Cyp1b1) expression is absent in mouse hepatocytes, but present in liver endothelia and activated stellate cells. Increased expression during adipogenesis suggests a role of Cyp1b1 metabolism in fatty acid homeostasis. Wild-type C57BL/6j (WT) and Cyp1b1-null (Cyp1b1-ko) mice were provided low or high fat diets (LFD and HFD, respectively). Cyp1b1-deletion suppressed HFD-induced obesity, improved glucose tolerance and prevented liver steatosis. Suppression of lipid droplets in sinusoidal hepatocytes, concomitant with enhanced glycogen granules, was a consistent feature of Cyp1b1-ko mice. Cyp1b1 deletion altered the in vivo expression of 560 liver genes, including suppression of PPARγ, stearoyl CoA desaturase 1 (Scd1) and many genes stimulated by PPARα, each consistent with this switch in energy storage mechanism. Ligand activation of PPARα in Cyp1b1-ko mice by WY-14643 was, nevertheless, effective. Seventeen gene changes in Cyp1b1-ko mice correspond to mouse transgenic expression that attenuated diet-induced diabetes. The absence of Cyp1b1 in mouse hepatocytes indicates participation in energy homeostasis through extra-hepatocyte signaling. Extensive sexual dimorphism in hepatic gene expression suggests a developmental impact of estrogen metabolism by Cyp1b1. Suppression of Scd1 and increased leptin turnover support enhanced leptin participation from the hypothalamus. Cyp1b1-mediated effects on vascular cells may underlie these changes.

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Section: Resultsmentioning

confidence: 99%

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Larsen

Bushkofsky

Gorman

et al. 2015

Archives of Biochemistry and Biophysics

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“…*, p Ͻ 0.05. NOVEMBER 11, 2016 • VOLUME 291 • NUMBER 46 cenic acid from palmitoleic acid in hepatocytes (32,33), so it is possible that this enzyme is significantly reduced in Plin2-null animals on CD. We observed striking decreases in Elovl5 gene expression for knock-out animals on WD.…”

Section: Loss Of Plin2 Results In Altered Hepatic Neutral Lipid Profimentioning

confidence: 99%

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Libby¹,

Bales²,

Orlicky

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanPerilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in -3 and -6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease.

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“…Interestingly, adenoviral induction of hepatic Elovl5 was shown to promote lipolysis by increasing ATGL mRNA and protein expression [127]. Whether such ethanol-induced decrease in Elovl5 also is affecting ATGL expression and hepatic TAG turnover is another area of research that warrants further investigation.…”

Section: Changes In Hepatic Ld Structure Function and Metabolism Folmentioning

confidence: 99%

Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease

Natarajan

Rasineni

Ganesan

et al. 2017

CMP

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For more than 30 years, lipid droplets (LDs) were considered as an inert bag of lipid for storage of energy-rich fat molecules. Following a paradigm shift almost a decade ago, LDs are presently considered an active subcellular organelle especially designed for assembling, storing and subsequently supplying lipids for generating energy and membrane synthesis (and in the case of hepatocytes for VLDL secretion). LDs also play a central role in many other cellular functions such as viral assembly and protein degradation. Here, we have explored the structural and functional changes that occur in hepatic and adipose tissue LDs following chronic ethanol consumption in relation to their role in the pathogenesis of alcoholic liver injury.

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Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice

Cited by 48 publications

References 65 publications

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease

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