Identification and Characterization of HAOX1, HAOX2, and HAOX3, Three Human Peroxisomal 2-Hydroxy Acid Oxidases

Jones, Jacob M.; Morrell, James C.; Gould, Stephen J.

doi:10.1074/jbc.275.17.12590

Cited by 109 publications

(97 citation statements)

References 44 publications

(38 reference statements)

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“…In addition, several enzymes have been described that function as 2-OH acid oxidases and are expressed in various human tissues (27). However, the potential role of 2-OH fatty acids in mammalian metabolism is unclear, and 2-OH fatty acid concentrations high enough to activate GPR109B have not been described.…”

Section: Discussionmentioning

confidence: 99%

Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Ahmed

Tunaru

Langhans

et al. 2009

Journal of Biological Chemistry

105

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The orphan G-protein-coupled receptor GPR109B is the result of a recent gene duplication of the nicotinic acid and ketone body receptor GPR109A being found in humans but not in rodents. Like GPR109A, GPR109B is predominantly expressed in adipocytes and is supposed to mediate antilipolytic effects. Here we show that GPR109B serves as a receptor for the ␤-oxidation intermediate 3-OH-octanoic acid, which has antilipolytic activity on human but not on murine adipocytes. GPR109B is coupled to G i -type G-proteins and is activated by 2-and 3-OH-octanoic acid with EC 50 values of about 4 and 8 M, respectively. Interestingly, 3-OH-octanoic acid plasma concentrations reach micromolar concentrations under conditions of increased ␤-oxidation rates, like in diabetic ketoacidosis or under a ketogenic diet. These data suggest that the ligand receptor pair 3-OH-octanoic acid/GPR109B mediates in humans a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in ␤-oxidation rates.

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Section: Discussionmentioning

confidence: 99%

Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Ahmed

Tunaru

Langhans

et al. 2009

Journal of Biological Chemistry

105

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“…Promoter polymorphisms might, however, alter gene transcription. Our results therefore shed light on gene pathways controlled by the GK haplotype in BN.GK2k involving altered peroxisomal fatty acid oxidation (19), which may contribute to impaired glucose regulation in this congenic strain and in GK rats.…”

Section: Discussionmentioning

confidence: 99%

Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q

Wallace

Wallis

Collins

et al. 2004

Physiological Genomics

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Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q. Physiol Genomics 19: 1-10, 2004. First published July 20, 2004 doi:10.1152/physiolgenomics.00114.2004.-Genetic studies in human populations and rodent models have identified regions of human chromosome 1q21-25 and rat chromosome 2 showing evidence of significant and replicated linkage to diabetes-related phenotypes. To investigate the relationship between the human and rat diabetes loci, we fine mapped the rat locus Nidd/gk2 linked to hyperinsulinemia in an F2 cross derived from the diabetic (type 2) Goto-Kakizaki (GK) rat and the Brown Norway (BN) control rat, and carried out its genetic and pathophysiological characterization in BN.GK congenic strains. Evidence of glucose intolerance and enhanced insulin secretion in a congenic strain allowed us to localize the underlying diabetes gene(s) in a rat chromosomal interval of ϳ3-6 cM conserved with an 11-Mb region of human 1q21-23. Positional diabetes candidate genes were tested for transcriptional changes between congenics and controls and sequence variations in a panel of inbred rat strains. Congenic strains of the GK rats represent powerful novel models for accurately defining the pathophysiological impact of diabetes gene(s) at the locus Nidd/gk2 and improving functional annotations of diabetes candidates in human 1q21-23. type 2 diabetes mellitus; genetics; comparative genomics THE INBRED GOTO-KAKIZAKI (GK) rat strain is a well-characterized nonobese model of spontaneous type 2 diabetes mellitus (T2DM), which is widely used for investigating important aspects of the pathogenesis of diabetes (1, 28) and mapping quantitative trait loci (QTL) involved in altered regulation of glucose and insulin levels. Replicated linkage between diabetes phenotypes and rat chromosome (RNO) 2 is suggested by results from QTL mapping studies in crosses derived from GK and the nondiabetic Brown Norway (BN) (13) or F344 rats (10) (loci Nidd/gk2 and Niddm2, respectively) and more recently in a cross involving the spontaneously diabetic Torii (SDT) rat, a new inbred model of nonobese type 2 diabetes (25).Comparative genome analyses have highlighted the possible conservation of synteny homology between the Nidd/gk2 region and human chromosome 1q21-24 (3), which shows evidence of replicated linkage to T2DM in at least eight populations, including European Americans (7), French whites (34), the UK Warren 2 repository (37), Pima Indians (17), and Chinese (38). This region is therefore the focus of intense interest in T2DM genetics.Progress in the completion of the rat genome sequence (30) provides a unique opportunity to refine homology relationships between RNO2 and human 1q and take advantage of genome annotations for T2DM candidate gene identification. The integration of comparative genomics and studies in rat congenic strains, which are designed to fine map QTL and test the phenotypic impact of gene variants in well-characterized re...

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“…6,7 However, these drugs either lack sufficient efficacy or are associated with significant adverse effects. In a search for a novel antihypertensive target, we have identified L-2-hydroxy acid oxidase (Hao2) 8 as a potential target for pharmacological intervention.…”

mentioning

confidence: 99%

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

Barawkar¹,

Meru²,

Bandyopadhyay³

et al. 2011

ACS Med. Chem. Lett.

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L-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetatetreated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension. KEYWORDS: Hao2, hypertension, pyrazolecarboxylic acid, DOCA rat H uman hypertension is a complex, multifactorial disorder resulting from the interplay of multiple environmental and genetic factors, and this common disorder can lead to an increased risk of heart attack, stroke, and renal failure. The mechanisms underlying the initiation and maintenance of the hypertensive process remain unclear. 1 Almost one-third of the U.S. adult population has high blood pressure (BP), which increases the risk of cardiovascular and renal disease and shortened life expectancy. 2−4 Various antihypertensive drugs have been developed, including diuretics, beta blockers, calcium channel blockers (CCBs), renin inhibitors, 5 angiotensinconverting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). 6,7 However, these drugs either lack sufficient efficacy or are associated with significant adverse effects. In a search for a novel antihypertensive target, we have identified L-2-hydroxy acid oxidase (Hao2) 8 as a potential target for pharmacological intervention.L-2-Hydroxy acid oxidases are flavin mononucleotide (FMN)-dependent peroxisomal enzymes, which are members of the flavoenzyme family that are responsible for the oxidation of a number of L-2-hydroxy acids to ketoacids at the expense of molecular oxygen, resulting in the formation of hydrogen peroxide. Several examples of such enzymes have been identified in different organisms, e.g., glycolate oxidase from plants, lactate oxidase from Mycobacterium (L-lactate 2-monooxygenase), flavocytochrome b 2 from yeasts (L-lactate cytochrome c oxidoreductase), and mandelate dehydrogenase from Pseudomonas putida. 9 In mammals, this family of enzymes was first identified as an L-amino acid oxidase in the kidney and the liver of rats and later found to have activity similar to that of L-2-hydroxy acid. 10,11 Two α-hydroxy acid oxidases were also reported from hog renal cortex, named long chain L-α-hydroxy acid oxidase (Hao2) and short chain L-α-hydroxy acid oxidase (Hao1), because of their substrate specificity toward long and short carbon chain L-α-hydroxy acids, respectively. In both prokaryotes and eukaryotes, all the memb...

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Identification and Characterization of HAOX1, HAOX2, and HAOX3, Three Human Peroxisomal 2-Hydroxy Acid Oxidases

Cited by 109 publications

References 44 publications

Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

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