Breakdown of 2-Hydroxylated Straight Chain Fatty Acids via Peroxisomal 2-Hydroxyphytanoyl-CoA Lyase

Foulon, Veerle; Sniekers, Mieke; Huysmans, Els; Asselberghs, Stanny; Mahieu, Vincent; Mannaerts, Guy P.; Veldhoven, Paul P. Van; Casteels, Minne

doi:10.1074/jbc.m413362200

Cited by 96 publications

(97 citation statements)

References 44 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A possible explanation for this increase would be the fact that a-hydroxy-substituted fatty acids cannot be straightforwardly metabolized via the b-oxidation pathway but must first be degraded by an enzyme pertaining to the a-oxidation pathway, that is, 2-hydroxyphytanoyl-CoA lyase. 14 The latter may become rapidly saturated, as it represents a secondary oxidation pathway for non-abundant natural fatty acids and, as a consequence, 2-OHOA may accumulate to a much higher degree in treated rats than oleic acid, which is predominantly used as a source of energy. This idea would also be in agreement with the observation that 2-OHOA started to be effective at lower doses than oleic acid, concerning the reduction of body weight.…”

Section: Discussionmentioning

confidence: 99%

Structure–effect relation of C18 long-chain fatty acids in the reduction of body weight in rats

et al. 2007

View full text Add to dashboard Cite

Objective: To investigate the relationship between chemical structure and physiological effect, the efficacy and the molecular mechanisms involved in the reduction of body weight by C18 fatty acids (stearic, elaidic, oleic, linoleic and 2-hydroxyoleic acids (2-OHOA)). Design: Ad libitum fed, lean Wistar Kyoto rats treated orally with up to 600 mg kg À1 of the fatty acids or vehicle every 12 h for 7 days. Besides, starved rats and rats pairfed to the 2-OHOA-treated group served as additional controls under restricted feeding conditions. Measurements: Body weight, food intake, weight of various fat depots, plasma leptin, hypothalamic neuropeptides, uncoupling proteins (UCP) in white (WAT) and brown adipose tissue (BAT) and phosphorylation level of cyclic AMP (cAMP) response element-binding protein (CREB) in WAT. Results: Only treatment with oleic acid and 2-OHOA induced body weight loss (3.3 and 11.4%, respectively) through reduction of adipose fat mass. Food intake in these rats was lower, although hypothalamic neuropeptide and plasma leptin levels indicated a rise in orexigenic status. Rats pairfed to the 2-hydroxyoleic group only lost 6.3% body weight. UCP1 expression and phosphorylation of CREB was drastically increased in WAT, but not BAT of 2-OHOA-treated rats, whereas no UCP1 expression could be detected in WAT of rats treated with oleic acid. Conclusion: Both cis-configured monounsaturated C18 fatty acids (oleic acid and 2-OHOA) reduce body weight, but the introduction of a hydroxyl group in position 2 drastically increases loss of adipose tissue mass. The novel molecular mechanism unique to 2-hydroxyoleic, but not oleic acid, implies induction of UCP1 expression in WAT by the cAMP/PKA pathwaydependent transcription factor CREB, most probably as part of a transdifferentiation process accompanied by enhanced energy expenditure.

show abstract

Section: Discussionmentioning

confidence: 99%

Structure–effect relation of C18 long-chain fatty acids in the reduction of body weight in rats

et al. 2007

View full text Add to dashboard Cite

show abstract

“…This is the site of fatty acid ␣-oxidation (20), which, in the present case, forms [ 13 C]formate from 4-hydroxynonanoate labeled on C-3. Given the low labeling of acetyl-CoA and its proxies formed from 4-hydroxy [3][4][5][6][7][8][9][10][11][12][13] C]nonanoate (Fig.…”

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

“…The first pathway, which involves 4-hydroxy-4-phosphoacyl-CoAs (4-Pacyl-CoAs), 3 leads to the formation of 3-hydroxyacyl-CoAs, which are physiological ␤-oxidation intermediates. The second pathway is a sequence of ␤-oxidation, ␣-oxidation (20,21), and ␤-oxidation steps. Via the two pathways, 4-hydroxyacids with five or more carbons are degraded to acetyl-CoA, propionylCoA, and formate.…”

mentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ). We investigated the catabolism of these compounds using a combination of metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations of unlabeled and labeled saturated 4-hydroxyacids (C 4 to C 11 ) or 4-hydroxynonenal. All the compounds tested form a new class of acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem mass spectrometry, accurate mass spectrometry, and 31 P-NMR. All 4-hydroxyacids with five or more carbons are metabolized by two new pathways. The first and major pathway, which involves 4-hydroxy-4-phosphoacylCoAs, leads in six steps to the isomerization of 4-hydroxyacylCoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological ␤-oxidation. The second and minor pathway involves a sequence of ␤-oxidation, ␣-oxidation, and ␤-oxidation steps. In mice deficient in succinic semialdehyde dehydrogenase, high plasma concentrations of 4-hydroxybutyrate result in high concentrations of 4-hydroxy-4-phospho-butyryl-CoA in brain and liver. The high concentration of 4-hydroxy-4-phospho-butyryl-CoA may be related to the cerebral dysfunction of subjects ingesting 4-hydroxybutyrate and to the mental retardation of patients with 4-hydroxybutyric aciduria. Our data illustrate the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.4-Hydroxy-n-acids are involved in different areas of mammalian metabolism. Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3, 4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1, 5-11). However, the catabolism of its carbon skeleton has not been unraveled. The four-carbon 4-hydroxybutyrate is a physiological neurotransmitter derived from ␥-aminobutyrate. Humans with inborn disorder of succinic semialdehyde dehydrogenase have high 4-hydroxybutyrate concentrations in body fluids, mental retardation, and seizures (12). 4-Hydroxybutyrate is also a drug of abuse that impairs the capacity to exercise judgment for unknown reasons. 4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14, 15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16). The calcium salt of a compound closely related to 4-hydroxypentanoate, levulinate (4-ketopentanoate, 4-ketovalerate), is used as an oral or intravenous source of calcium in humans.We conducted a study on the catabolism of C 4 to C 11 4-hydroxyacids in perfused rat livers using a combination of metabolomics (17,18) and mass isotopomer analysis 2 (19)....

show abstract

“…To date, only peroxisomal FA α-oxidation has been described in mammals (2,28). The 2-OH acyl-CoA lyase HACL1, which is localized in the peroxisomes, has been shown to be involved in the cleavage (C1 removal) step of the FA α-oxidation that is composed of three reactions (CoA addition, cleavage, and oxidation) (3,4,29). Here, we show that the HACL1 homolog HACL2 (2-hydroxyacyl-CoA lyase 2) [previous name, ILVBL; ilvB (bacterial acetolactate synthase)-like], which is localized in the ER, is mainly involved in the C1 removal reaction of the FA α-oxidation in the PHS degradation pathway.…”

Section: Significancementioning

confidence: 99%

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Kitamura

Seki

Kihara

2017

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

View full text Add to dashboard Cite

Although normal fatty acids (FAs) are degraded via β-oxidation, unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs are degraded via α-oxidation. Phytosphingosine (PHS) is one of the long-chain bases (the sphingolipid components) and exists in specific tissues, including the epidermis and small intestine in mammals. In the degradation pathway, PHS is converted to 2-OH palmitic acid and then to pentadecanoic acid (C15:0-COOH) via FA α-oxidation. However, the detailed reactions and genes involved in the α-oxidation reactions of the PHS degradation pathway have yet to be determined. In the present study, we reveal the entire PHS degradation pathway: PHS is converted to C15:0-COOH via six reactions [phosphorylation, cleavage, oxidation, CoA addition, cleavage (C1 removal), and oxidation], in which the last three reactions correspond to the α-oxidation. The aldehyde dehydrogenase ALDH3A2 catalyzes both the first and second oxidation reactions (fatty aldehydes to FAs). In Aldh3a2-deficient cells, the unmetabolized fatty aldehydes are reduced to fatty alcohols and are incorporated into ether-linked glycerolipids. We also identify HACL2 (2-hydroxyacyl-CoA lyase 2) [previous name, ILVBL; ilvB (bacterial acetolactate synthase)-like] as the major 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the FA α-oxidation of the PHS degradation pathway. HACL2 is localized in the endoplasmic reticulum. Thus, in addition to the already-known FA α-oxidation in the peroxisomes, we have revealed the existence of FA α-oxidation in the endoplasmic reticulum in mammals.α-oxidation | fatty acid | metabolism | lipid | sphingolipid M ost cellular fatty acids (FAs) have a nonhydroxylated straight chain and are degraded via β-oxidation either in the mitochondria for long-chain FAs (C11-C20), or in the peroxisomes for very long-chain FAs (≥C21) (1, 2). However, unusual FAs, such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs (i.e., food-derived phytanic acid), are degraded via α-oxidation (2-4). During FA synthesis by FA synthase type I, acetyl-acyl carrier proteins (ACPs) receive two-carbon units from malonyl-ACP seven times to produce palmitoyl-ACP, followed by thioester bond cleavage to release palmitic acid (C16:0-COOH) (5). Some of the cellular FAs are further elongated via the FA elongation cycle in the endoplasmic reticulum (ER). In each cycle, the FA chain length is elongated by two (6, 7). In the FA degradation pathway (β-oxidation), the FA chain length is shortened by two as acetylCoA is released (1). Thus, all FA synthesis, elongation, and degradation steps proceed by two-carbon units. Accordingly, most cellular FAs are even-numbered. However, odd-numbered FAs also exist, albeit at much lower levels, because α-oxidation produces odd-numbered FAs from 2-OH FAs (8, 9).Sphingolipids are one of the major lipid classes in eukaryotes. The sphingolipid backbone ceramide (CER) is composed of a longchain base (LCB) and an FA (10, 11). Although the FA moiety of CERs is nonhydroxylated in most tissues, CERs...

show abstract

Breakdown of 2-Hydroxylated Straight Chain Fatty Acids via Peroxisomal 2-Hydroxyphytanoyl-CoA Lyase

Cited by 96 publications

References 44 publications

Structure–effect relation of C18 long-chain fatty acids in the reduction of body weight in rats

Structure–effect relation of C18 long-chain fatty acids in the reduction of body weight in rats

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Contact Info

Product

Resources

About