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The role of alpha-methylacyl-CoA racemase in bile acid synthesis.

ABSTRACT: According to current views, the second peroxisomal beta-oxidation pathway is responsible for the degradation of the side chain of bile acid intermediates. Peroxisomal multifunctional enzyme type 2 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(R)-3-hydroxyacyl-CoA dehydrogenase; MFE-2] catalyses the second (hydration) and third (dehydrogenation) reactions of the pathway. Deficiency of MFE-2 leads to accumulation of very-long-chain fatty acids, 2-methyl-branched fatty acids and C(27) bile acid intermediates in plasma, but bile acid synthesis is not blocked completely. In this study we describe an alternative pathway, which allows MFE-2 deficiency to be overcome. The alternative pathway consists of alpha-methylacyl-CoA racemase and peroxisomal multifunctional enzyme type 1 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(S)-3-hydroxyacyl-CoA dehydrogenase; MFE-1]. (24E)-3alpha,7alpha,12alpha-Trihydroxy-5beta-cholest-24-enoyl-CoA, the presumed physiological isomer, is hydrated by MFE-1 with the formation of (24S,25S)-3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA [(24S,25S)-24-OH-THCA-CoA], which after conversion by a alpha-methylacyl-CoA racemase into the (24S,25R) isomer can again be dehydrogenated by MFE-1 to 24-keto-3alpha,7alpha,12alpha-trihydroxycholestanoyl-CoA, a physiological intermediate in cholic acid synthesis. The discovery of the alternative pathway of cholesterol side-chain oxidation will improve diagnosis of peroxisomal deficiencies by identification of serum 24-OH-THCA-CoA diastereomer profiles.

SUBMITTER: Cuebas DA

PROVIDER: S-EPMC1222534 | biostudies-other | 2002 May

REPOSITORIES: biostudies-other

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Asymptomatic retinal dysfunction in alpha-methylacyl-CoA racemase deficiency.

Project description:PurposeAlpha-methylacyl-CoA racemase (AMACR) deficiency is a peroxisomal disorder due to biallelic mutations in AMACR. At least 13 genetically confirmed patients have been reported to date. Seven had obvious pigmentary retinopathy; however, for the other six, no retinal phenotype was mentioned. The purpose of this report is to document subtle retinal findings in an additional affected family.MethodsRetrospective case series (three affected siblings and their unaffected parents).ResultsThree Arab siblings (16, 19, and 22 years old) with prior juvenile cholelithiasis had been diagnosed with AMACR deficiency based on biochemical analysis, whole exome sequencing, and confirmatory segregation analysis (AMACR NM_001167595.1: c.877T>C; p.C293R). For all three, there were no visual complaints, but retinal multimodal imaging and electroretinography suggested subtle retinal dysfunction.ConclusionsRetinal dysfunction is a parameter that should be measured in patients with known or suspected AMACR deficiency even in the absence of visual symptoms. This may be helpful with clinical diagnosis and monitoring response to dietary interventions.

| S-EPMC8254661 | biostudies-literature

Alpha-Methylacyl-CoA Racemase (AMACR), a Potential New Biomarker for Glioblastoma.

Project description:Alpha-Methylacyl-CoA racemase (AMACR), which was initially discovered as a prostate cancer marker, is critical for the chiral inversion mechanism of branched-chain fatty acids. However, the function of AMACR in brain tumors has not been investigated. In this study, AMACR appeared to be involved in glioblastoma. The protein and mRNA levels of AMACR were highly elevated in glioblastoma. Downregulation of AMACR inhibited cell proliferation. Comprehensive analysis of the public REMBRANDT GBM dataset also confirmed that the level of AMACR expression was correlated with the clinical prognosis of glioma patients. In summary, these findings indicate that AMACR expression is increased in a glioblastoma cell line and glioma patients, suggesting that AMACR might be a potential diagnostic marker and therapeutic target for cancer, including glioma.

| S-EPMC7590573 | biostudies-literature

Expression and characterization of α-methylacyl CoA racemase from Anisakis simplex larvae.

Project description:Larval excretory-secretory products of Anisakis simplex are known to cause allergic reactions in humans. A cDNA library of A. simplex 3rd-stage larvae (L3) was immunoscreened with polyclonal rabbit serum raised against A. simplex L3 excretory-secretory products to identify an antigen that elicits the immune response. One cDNA clone, designated as α-methylacyl CoA racemase (Amacr) contained a 1,412 bp cDNA transcript with a single open reading frame that encoded 418 amino acids. A. simplex Amacr showed a high degree of homology compared to Amacr orthologs from other species. Amacr mRNA was highly and constitutively expressed regardless of temperature (10-40℃) and time (24-48 hr). Immunohistochemical analysis revealed that Amacr was expressed mainly in the ventriculus of A. simplex larvae. The Amacr protein produced in large quantities from the ventriculus is probably responsible for many functions in the development and growth of A. simplex larvae.

| S-EPMC3375458 | biostudies-literature

Diagnosis in bile acid-CoA: amino acid N-acyltransferase deficiency.

Project description:Cholate-CoA ligase (CCL) and bile acid-CoA: amino acid N-acyltransferase (BAAT) sequentially mediate bile-acid amidation. Defects can cause intrahepatic cholestasis. Distinction has required gene sequencing. We assessed potential clinical utility of immunostaining of liver for CCL and BAAT. Using commercially available antibodies against BAAT and CCL, we immunostained liver from an infant with jaundice, deficiency of amidated bile acids, and transcription-terminating mutation in BAAT. CCL was normally expressed. BAAT expression was not detected. Immunostaining may facilitate diagnosis in bile-acid amidation defects.

| S-EPMC3391772 | biostudies-literature

MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.

Project description:BACKGROUND: Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. METHODS: We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. RESULTS: A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367?G>A [p.Asp123Asn] mutation in the ?-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of ?-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169??mol/L, normal <1.5??mol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients. CONCLUSIONS: Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset ?-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.

| S-EPMC3567975 | biostudies-literature

Hepatocyte peroxisome proliferator-activated receptor α regulates bile acid synthesis and transport.

Project description:Peroxisome proliferator-activated receptor alpha (PPARα) controls lipid homeostasis through regulation of lipid transport and catabolism. PPARα activators are clinically used for hyperlipidemia treatment. The role of PPARα in bile acid (BA) homeostasis is beginning to emerge. Herein, Ppara-null and hepatocyte-specific Ppara-null (Ppara∆Hep) as well as the respective wild-type mice were treated with the potent PPARα agonist Wy-14,643 (Wy) and global metabolomics performed to clarify the role of hepatocyte PPARα in the regulation of BA homeostasis. Levels of all serum BAs were markedly elevated in Wy-treated wild-type mice but not in Ppara-null and Ppara∆Hep mice. Gene expression analysis showed that PPARα activation (1) down-regulated the expression of sodium-taurocholate acid transporting polypeptide and organic ion transporting polypeptide 1 and 4, responsible for the uptake of BAs into the liver; (2) decreased the expression of bile salt export pump transporting BA from hepatocytes into the bile canaliculus; (3) upregulated the expression of multidrug resistance-associated protein 3 and 4 transporting BA from hepatocytes into the portal vein. Moreover, there was a notable increase in the compositions of serum, hepatic and biliary cholic acid and taurocholic acid following Wy treatment, which correlated with the upregulated expression of the Cyp8b1 gene encoding sterol 12α-hydroxylase. The effects of Wy were identical between the Ppara∆Hep and Ppara-null mice. Hepatocyte PPARα controlled BA synthesis and transport not only via direct transcriptional regulation but also via crosstalk with hepatic farnesoid X receptor signaling. These findings underscore a key role for hepatocyte PPARα in the control of BA homeostasis.

| S-EPMC7423166 | biostudies-literature

Identification of a novel function of hepatic long-chain acyl-CoA synthetase-1 (ACSL1) in bile acid synthesis and its regulation by bile acid-activated farnesoid X receptor.

Project description:Long-chain acyl-CoA synthetase 1 (ACSL1) plays a pivotal role in fatty acid β‑oxidation in heart, adipose tissue and skeletal muscle. However, key functions of ACSL1 in the liver remain largely unknown. We investigated acute effects of hepatic ACSL1 deficiency on lipid metabolism in adult mice under hyperlipidemic and normolipidemic conditions. We knocked down hepatic ACSL1 expression using adenovirus expressing a ACSL1 shRNA (Ad-shAcsl1) in mice fed a high-fat diet or a normal chow diet. Hepatic ACSL1 depletion generated a hypercholesterolemic phenotype in mice fed both diets with marked elevations of total cholesterol, LDL-cholesterol and free cholesterol in circulation and accumulations of cholesterol in the liver. Furthermore, SREBP2 pathway in ACSL1 depleted livers was severely repressed with a 50% reduction of LDL receptor protein levels. In contrast to the dysregulated cholesterol metabolism, serum triglycerides, free fatty acid and phospholipid levels were unaffected. Mechanistic investigations of genome-wide gene expression profiling and pathway analysis revealed that ACSL1 depletion repressed expressions of several key enzymes for bile acid biosynthesis, consequently leading to reduced liver bile acid levels and altered bile acid compositions. These results are the first demonstration of a requisite role of ACSL1 in bile acid biosynthetic pathway in liver tissue. Furthermore, we discovered that Acsl1 is a novel molecular target of the bile acid-activated farnesoid X receptor (FXR). Activation of FXR by agonist obeticholic acid repressed the expression of ACSL1 protein and mRNA in the liver of FXR wild-type mice but not in FXR knockout mice.

| S-EPMC6604619 | biostudies-literature

Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity.

Project description:Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity.The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis.We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals.We analyzed serum BAs and markers of BA synthesis after overnight fasting, during a hyperinsulinemic-euglycemic clamp, or a mixed-meal tolerance test and the association of BA transporter expression with body mass index.BA synthesis markers were 2-fold higher (P < .01) and preferentially 12?-hydroxylated (P < .05) in obese subjects, and both measures were correlated with clamp-derived insulin sensitivity (r = -0.62, P < .0001, and r = -0.39, P = .01, respectively). Insulin infusion acutely reduced serum BAs in nonobese subjects, but this effect was blunted in obese subjects (?BAs -44.2% vs -4.2%, P < .05). The rise in serum BAs postprandially was also relatively blunted in obese subjects (?BAs +402% vs +133%, P < .01). Liver expression of the Na+-taurocholate cotransporting polypeptide and the bile salt export pump were negatively correlated with body mass index (r = -0.37, P = .02, and r = -0.48, P = .001, respectively).Obesity is associated with increased BA synthesis, preferential 12?-hydroxylation, and impaired serum BA fluctuations. The findings reveal new pathophysiological aspects of BA action in obesity that may lend themselves to therapeutic targeting in metabolic disease.

| S-EPMC4870845 | biostudies-literature

Prostate Cancer Diagnosis Using Urine Sediment Analysis-Based α-Methylacyl-CoA Racemase Score: A Single-Center Experience.

Project description:To evaluate the diagnostic value of α-methylacyl-CoA racemase (AMACR) score in Han Chinese patients with prostate cancer (PCa) through urine sediment analysis. We collected 292 urine sediment samples after digital rectal examination. Levels of AMACR and prostate-specific antigen (PSA) messenger RNA (mRNAs) were evaluated by quantitative real time-polymerase chain reaction. The diagnostic value of AMACR score was assessed by receiver-operating characteristic analysis (ROC), Mann-Whitney test, logistic regression analysis and decision curve analysis. In all patients (n = 292), the area under the curve (AUC) for serum PSA, AMACR score, and a combinative model of these 2 parameters were 0.745 (95% confidence interval [CI]: 0.691-0.794), 0.753 (95% CI: 0.700-0.802), and 0.784 (95% CI: 0.732-0.830). No statistical difference was found between AMACR score and serum PSA (P = .826), while the combinative model was better than AMACR score (Z = 5.222, P < .001). Among patients with serum PSA level of 4 to 10 ng/mL (n = 121), the AMACR score was significantly higher in patients with PCa (P = 0.0002), while serum PSA showed no difference (P = 0.3023). Alpha-methylacyl-CoA racemase score (AUC = 0.712, 95% CI: 0.623-0.790) and a combinative model (AUC = 0.714, 95% CI: 0.626-0.793) showed a better diagnostic value than serum PSA (AUC = 0.559, 95% CI: 0.466-0.649), (P = .048, P = .042). Decision curve analysis showed a biopsy prediction model including AMACR score have a better net benefit when the threshold probability greater than 20%. The diagnostic model combing serum PSA and AMACR score has a better diagnostic value in patients with abnormal PSA level (including PSA level ranging from 4-10 ng/mL), and could reduce unnecessary prostate biopsy in clinical use.

| S-EPMC6891009 | biostudies-literature

α-Methylacyl-CoA racemase (AMACR) serves as a prognostic biomarker for the early recurrence/metastasis of HCC.

Project description:AimsHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it is still lacking effective prognostic biomarkers so far. Previous results of the iTRAQ-based quantitative proteomics study (iTRAQ-2DLC-MS/MS) have shown that α-methylacyl-CoA racemase (AMACR) might be a promising prognostic biomarker for the early recurrence/metastasis of hepatocellular carcinoma (HCC). Here a large-scale cohort clinical study was performed to evaluate its prognostic potential.MethodsHCC samples from patients (n=158) were used for the construction of tissue microarray. The expression level of AMACR was determined by immunohistochemical staining. A large-scale cohort clinical study between the expression of AMACR and some major clinical parameter has been performed to assess the prognostic potential of AMACR for the early recurrence/metastasis of HCC.ResultsSome important clinical parameters such as α-fetoprotein, tumour numbers, dissemination to regional lymph nodes, tumour capsule and portal vein tumour thrombosis are significantly associated with the low expression of AMACR. The expression of AMACR was an independent factor for the survival of patients with HCC. The median survival time was 17 months in the low-expression group compared with 45 months in the high-expression group.ConclusionsThis study reveals that the AMACR might be a potential prognostic marker for predicting early recurrence/metastasis of HCC after hepatectomy.

| S-EPMC4215266 | biostudies-literature

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