Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases

Hardwick, James P.

doi:10.1016/j.bcp.2008.03.004

Cited by 251 publications

(217 citation statements)

References 65 publications

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“…The majority of these are relatively upregulated in the high IMF Wagyu. Having said this, the single largest discriminator between the breeds was CYP4F2, a monooxygenase that can inactivate leukotriene B4, a mediator of inflammation (Hardwick, 2008). This molecule is relatively upregulated in the Piedmontese.…”

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

“…This molecule is relatively upregulated in the Piedmontese. Its role in metabolising both pro-and anti-inflammatory agents indicates it may function in both the activation and resolution of inflammation (Hardwick, 2008). CYP4F2 is also involved in long chain and very long chain fatty acid metabolism whereupon the hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolised in the peroxisome to shorter chain fatty acids that in turn can be processed in the mitochondrion (Hardwick, 2008).…”

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

“…Its role in metabolising both pro-and anti-inflammatory agents indicates it may function in both the activation and resolution of inflammation (Hardwick, 2008). CYP4F2 is also involved in long chain and very long chain fatty acid metabolism whereupon the hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolised in the peroxisome to shorter chain fatty acids that in turn can be processed in the mitochondrion (Hardwick, 2008). CYP4F2 has high affinity for arachidonic acid (Hardwick, 2008), a compound previously explored in the marbling literature, and is also responsive to RA stimulation (Kalsotra et al, 2008).…”

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

“…CYP4F2 is also involved in long chain and very long chain fatty acid metabolism whereupon the hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolised in the peroxisome to shorter chain fatty acids that in turn can be processed in the mitochondrion (Hardwick, 2008). CYP4F2 has high affinity for arachidonic acid (Hardwick, 2008), a compound previously explored in the marbling literature, and is also responsive to RA stimulation (Kalsotra et al, 2008). Given the strong relationship between inflammation and adiposity, the observation that an inhibitor of inflammation is relatively downregulated in the high fat, pro-inflammatory Wagyu is noteworthy.…”

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

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Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Hudson

Reverter

Greenwood

et al. 2015

Animal

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Intramuscular fat (IMF) can improve meat product quality through its impact on flavour and juiciness. High marbling cuts can command premium prices in some countries and grading systems, but there is substantial cost involved in choosing to grain feed animals in an effort to deposit more IMF. There would be value in developing methods to predict predisposition to 'marble' well. Unfortunately, the biological mechanisms underpinning marbling remain a mystery: the key adipocyte cell populations have not been defined, there are no reliable DNA markers, no known (if any) causal mutations and gene expression analyses in the main have tended to characterise increases in expression of end-point fat metabolism proteins such as the fatty acid-binding proteins. To shed light on expression-based markers of marbling potential, we contrasted LD gene expression in high IMF Wagyu cross animals with a low IMF Piedmontese cross at various time points. The expected divergence in the fat metabolism genes FABP4, THRSP, CIDEC and ACACA between the breeds occurs surprisingly late in postnatal development at about 20 months. On the other hand, divergent expression of WISP2, RAI14 and CYP4F2 was discovered in animals at or before 12 months of age, suggesting these genes may have potential as earlier predictors of marbling potential. In line with other researchers, we found intriguing links between IMF development and connective tissue remodelling. WISP2 -a novel adipokine highly expressed and secreted by adipose precursor cells and an inhibitor of the pro-fibrotic connective tissue growth factor -emerges as a particularly attractive candidate. It is relatively upregulated in high marbling Wagyu before admission to feedlotting, somewhere between 7 and 12 months. This difference is subsequently maintained until 25 months, but not thereafter. RAI14, thought to play a role in porcine adipocyte differentiation and with links to retinoic acid metabolism, has an unusual expression profile. Its expression level increases monotonically with postnatal development, and is always higher in Wagyu than Piedmontese. Strong, sustained upregulation of the anti-inflammatory CYP4F2 in Piedmontese is consistent with Wagyu adiposity being a pro-inflammatory state. Application of regulatory impact factor analysis, a network method for identifying causal effector molecules, suggests marbling roles for transcription factors previously implicated in (1) the formation of liposarcoma (unconstrained fatty masses) (YEATS4, MDM2), (2) adipogenesis (CREBL2, SP1, STAT1) and (3) inflammation (ISGF3G, HOXB13, PML).

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Section: Marbling Physiology and Developmentmentioning

confidence: 99%

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

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Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Hudson

Reverter

Greenwood

et al. 2015

Animal

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“…Cytochrome P450 family 4 fatty acid -hydroxylases are heme-containing monooxygenases that provide pathways for the reduction of potentially toxic non-esterified fatty acids and for the elimination of excess nutritive and non-nutritive lipids by catalyzing the addition of oxygen to a C-H bond of the terminal -carbon of fatty acids (1,2). The resulting -alcohols are generally oxidized further to produce dicarboxylic acids, but they also may be transformed to glucuronides or esterified to glycerolipids.…”

mentioning

confidence: 99%

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

Hsu

Baer

Rettie

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeP450 family 4 fatty acid -hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for -hydroxylation. The structure indicated that octane is bound in a narrow active-site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for -hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized Glu-310 contributes to substrate positioning. The preference for -hydroxylation was decreased in an E310A mutant having a shorter side chain, but the overall rates of metabolism were retained. E310D and E310Q substitutions having longer side chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane -hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for -hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for -hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of unactivated primary C-H bonds.Cytochrome P450 family 4 fatty acid -hydroxylases are heme-containing monooxygenases that provide pathways for the reduction of potentially toxic non-esterified fatty acids and for the elimination of excess nutritive and non-nutritive lipids by catalyzing the addition of oxygen to a C-H bond of the terminal -carbon of fatty acids (1, 2). The resulting -alcohols are generally oxidized further to produce dicarboxylic acids, but they also may be transformed to glucuronides or esterified to glycerolipids. Urinary dicarboxylic fatty acids are elevated in humans by fasting or in uncontrolled diabetes, which are conditions where adipocyte lipolysis increases the availability of non-esterified fatty acids to fuel metabolism (3). It is estimated that roughly 15% of fatty acids undergo -hydroxylation during peak periods of fatty acid catabolism (4), whereas this fraction is much smaller under conditions where concentrations of nonesterified fatty acids are low (5). Collectively, these enzymes provide pathways for the metabolic clearance of branched chain fatty acids, eicosanoids, and xenobiotic substrates such as dietary phytanic acid, drugs, toxins, and vitamins E and K (1, 2, 6).Similar to other P450 2 gene families encoding multipurpose enzymes for the elimination of xenobiotic compounds, family 4 exhibits genetic diversi...

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Structure and Function of Cytochrome P450 Enzymes

Montellano¹,

Paul²

2012

Encyclopedia of Drug Metabolism and Interactions

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Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases

Cited by 251 publications

References 65 publications

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

Structure and Function of Cytochrome P450 Enzymes

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