carnitine palmitoyltransferase 1 function

2011 May 1;435(3):723-32. doi: 10.1042/BJ20101680. Hepatic malonyl-CoA concentration is very low during suckling. While significant controversy remains regarding the importance of carnitine during submaximal exercise, the role it plays during high-intensity exercise is somewhat clearer. Bruce CR, Hoy AJ, Turner N, Watt MJ, Allen TL, et al. CPT-1, an integral transmembrane protein of the mitochondrial outer membrane that catalyzes the transfer of acyl moieties from co-enzyme A (CoA) to carnitine; 2. the carnitine–acylcarnitine translocase (CACT) trans- Pyruvate carboxylase deficiency is a rare autosomal recessive disease that affects a variety of organs, including the liver, kidney, brain, skeletal muscle, heart, and adipose tissue. doi: 10.1210/endocr/bqz046. Inhibition of CPT1A induces phosphorylation and activation of the FoxO transcription factors, NLM Mechanisms explaining how varying exercise intensities can induce a shift in either the enzymatic preference of carnitine (CRAT vs. CPT-1) or the subcellular distribution of the carnitine pool (i.e., intramitochondrial to facilitate CRAT vs. extramitochondrial to promote CPT-1) that promote this switch in enzymatic preference are currently unknown. The mice are more prone to becoming obese on a high-fat diet and display reduced whole-body fatty acid oxidation. Organic aciduria is not prominent in this disorder, but hyperammonemia may be present. CPT1A deficiency presents clinically as fasting intolerance, with lethargy and a Reye-like picture of hepatic failure associated with hypoglycemia and failure of ketone production. From: International Review of Cell and Molecular Biology, 2018, Jeff Cobb, Iain Dukes, in Annual Reports in Medicinal Chemistry, 1998. METHODS: We subjected male adult rats to renal I/R by bilateral renal pedicle CPT-1a patients present with a severe hypoketotic hypoglycemia phenotype of early onset.75 There is little or no heart involvement because CPT-1b is the predominant isoform in heart and skeletal muscle. Jerry Vockley, in Emery and Rimoin's Principles and Practice of Medical Genetics, 2013. At rest, free carnitine is nearly four- to sixfold more abundant than acylcarnitines in skeletal muscle.73 During moderate-intensity exercise (50–65% VO2max), free carnitine levels decline, but still account for greater than half of the total carnitine pool (free carnitine + acylcarnitines).73 Evidence that carnitine may be limiting was found as provision of supplemental carnitine for 28 days enhanced fat oxidation during moderate-intensity exercise (66% VO2max) in humans.74 Furthermore, 24 weeks of carnitine supplementation significantly increased free carnitine content in skeletal muscle which was associated with greater preservation of glycogen stores following 50% VO2max exercise, suggesting an increased capacity to facilitate fat oxidation.73 While these studies lend credence to the notion that supplemental carnitine can enhance fat oxidation during moderate-intensity exercise, these findings are not universally supported as separate studies providing supplemental carnitine either acutely or for up to 4 weeks did not enhance fat oxidation.75–78 Currently, it is speculated that enhancing the duration of carnitine supplementation may facilitate fat oxidation during moderate-intensity exercise. CPT1 is a protein that is responsible for the translocation of fatty acids from the cytosol to the mitochondrial matrix, where FAO occurs. Nat Med. Severe bouts of rhabdomyolysis with myoglobinuria can cause acute renal failure. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. 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CPT I deficiency presents in infancy as attacks of fasting-induced life-threatening hypoketotic hypoglycemia. Carnitine function and requirements during the life cycle. CPT II deficiency is the most common of this group of disorders. Heterozygous knockout mice express half of the mRNA, half of the protein and have an intermediary phenotype (Wolfgang et al. Severe deficiency of liver CPT I is rare but more frequent milder variants have been identified in geographically restricted populations. Nat Rev Cancer. 6: 3379-3386; 1992. In general, molecular/genetic diagnosis is difficult because no single mutation is predominant and functional testing may be required to establish pathogenicity.6, Robert C. Noland, in Progress in Molecular Biology and Translational Science, 2015. Myopathy is not a typical manifestation but has been reported. The carnitine shuttle includes carnitine palmitoyltransferase 1 (CPT1), acylcarnitine translocase (CACT), and carnitine palmitoyltransferase 2 (CPT2), which allows LCFA-CoA to enter the mitochondrial matrix, via transesterification reactions, to then be beta-oxidized. Interestingly, in CPT-1a+/− mice, males show about 50% reduction in CPT-1 activity in the liver but females have normal activity. The control of fatty acid translocation across the mitochondrial membrane is mediated by the carnitine palmitoyltransferase (CPT) system. Cancer Res. Long-chain acylcarnitines may be elevated (145). However, a requirement for extended carnitine supplementation would suggest that the effects would likely be due to chronic remodeling of metabolic pathways, rather than acute changes in carnitine status that would modulate substrate selection during submaximal exercise. Oncogene. The adult form of CPT II deficiency is a common cause of exercise-induced myoglobinuria. The characteristic diagnostic finding in these patients is a low total plasma carnitine level with an increased acylcarnitine fraction and no dicarboxylic aciduria. During periods of fasting, long-chain fatty acids are an important energy source for the liver and other tissues. Because of the rate-limiting role of CPT-1 in mitochondrial fatty acid metabolism there has been much interest in studying the enzyme and developing means to pharmacologically control it for the treatment of heart disease, obesity, and the metabolic syndrome. Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase. Please enable it to take advantage of the complete set of features! 1 Publication However, its use soon plummeted after reports of hepatotoxicity and neurotoxicity in patients who metabolized perhexiline slowly.45 The metabolic derangement noted in heart failure raised the possibility that perhexiline may theoretically benefit patients with heart failure by directing energy production toward a more metabolically efficient substrate: glucose. Carnitine palmitoyltransferase 1 (CPT1) is the enzyme in the outer mitochondrial membrane that converts long-chain acyl-CoA species to their corresponding long-chain acyl-carnitines for transport into the mitochondria (see Fig. -, Gatenby RA, Gillies RJ. CPT1A inactivation cuases cell cycle…, Figure 3. Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. Epub 2010 May 26. Inhibition of CPT1A induces p21…, Figure 5. 2016 May 19;7(5):e2226. Plays an important role in triglyceride metabolism. 2.3.1.21) or the enzymes involved in β-oxidation is associated with contractile dysfunction due to skeletal and heart muscle damage. Modulation of its functionality has simultaneous effects on fatty acid and glucose metabolism. Clipboard, Search History, and several other advanced features are temporarily unavailable. Episodes can be severe enough to lead to acute renal failure. View Article PubMed/NCBI Carnitine palmitoyltransferase 1 (CPT1) is the enzyme in the outer mitochondrial membrane that converts long-chain acyl-CoA species to their corresponding long-chain acyl-carnitines for transport into the mitochondria (see Fig. Carnitine palmitoyltransferase 1 (CPT1) plays an essential role in maintaining energy supply via fatty acid oxidation, especially under fasting. Since CPT-1 activity requires carnitine (Fig. The enzyme is known to exist in three different isoforms: CPT1A is expressed in liver and kidney, CPT1B in cardiac and skeletal muscle, and CPT1C in the brain.  |  In both infantile forms, CPT II activity is less than 10% of normal. Establishing a relationship between prolactin and altered fatty acid β-oxidation via carnitine palmitoyl transferase 1 in breast cancer cells. Carnitine palmitoyltransferase 1 (CPT1), is an enzyme belonging to the family of carnitine acyl- transferases whose function is to transport the long chain fatty acids coupled with coenzyme A (LCFA-CoA), from the cytosol to the mitochondria where LCFA are β-oxidized to satisfy the need for the energy required in the body3. After 8 weeks, perhexiline-treated patients demonstrated a significant increase in LV function and peak exercise oxygen consumption in comparison with the placebo recipients. In the most severe form of the disease, patients die within the first few weeks of life. CPT1A knockdown decreases anchorage-independent growth…, Figure 4. CPT2 polymorphic variants do not cause classical carnitine palmitoyltransferase 2 deficiency, and patients harboring any of them are asymptomatic most of the time. Treatment for this disorder, as with all FAO disorders involves preventing flux through the FAO pathway as much as possible by preventing fasting and supplying carbohydrate support when necessary. Three forms of CPT II deficiency have been described: infantile, late infantile, and adult. View all proteins of this organism that are known to be involved in the pathway fatty acid beta-oxidation and in Lipid metabolism. Inhibition of CPT1A induces phosphorylation…, Figure 6. Patients with a more benign clinical course have since been identified, who have responded well to modest carnitine supplementation and dietary therapy (145,162). A functional peroxisome proliferator-activated receptor (PPAR) responsive element (PPRE) and a myocite-specific (MEF2) site that binds MEF2A and MEF2C in the promoter of this gene had been previously identified. Carnitine palmitoyltransferase I (CPT-1) is the rate limiting step in long-chain fatty acid oxidation. Regardless of the mechanism(s) through which carnitine modulates substrate metabolism during exercise, the substantial decrease in free carnitine during high-intensity exercise appears to limit fat oxidation. P.M. Jones, M.J. Bennett, in Biomarkers in Inborn Errors of Metabolism, 2017. CPT II deficiency, in contrast to CPT I deficiency, has variable clinical manifestations. Carnitine content reflects the FA oxidative capacity of the tissue (i.e., oxidative tissues have greater carnitine reserves). Deficiency of either CPT-1a or -1b is lethal in the mouse.78,79 Heterozygotes have been phenotyped and do display some features of fatty acid oxidation disorders. P30 CA016059/CA/NCI NIH HHS/United States, R01 CA061774/CA/NCI NIH HHS/United States, R01 CA102196/CA/NCI NIH HHS/United States, 2R01CA102196/CA/NCI NIH HHS/United States, NCI CPTC Antibody Characterization Program, Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. 2020 Aug 13;12(8):2269. doi: 10.3390/cancers12082269. pmid:19073774 . Carnitine was detected at the beginning of this century, but it was nearly forgotten among biochemists until its importance in fatty acid metabolism was established 50 years later. 2011;17:1498–1503. In combination with its large mass, estimates indicate that nearly 95% of the total carnitine pool within the body lies within skeletal muscle.71 Free carnitine does not change during low-intensity exercise (< 40% VO2max); however, beyond this point levels progressively diminish with increasing intensity and the decrease can be approximately two- to fivefold after heavy exercise.6,72 Since carnitine is necessary to facilitate mitochondrial FA uptake, these robust decreases in free carnitine levels led researchers to predict that free carnitine availability may become limiting as workload increases, thereby providing a potential explanation for the differences in fat oxidation observed at varying exercise intensity. Ji Z, Shen Y, Feng X, Kong Y, Shao Y, Meng J, Zhang X, Yang G. Front Oncol. Females apparently have a means of compensating for the loss of one CPT-1a allele. The hypoglycemic episodes manifest as lethargy, coma, seizures, and may cause death. Endocrinology. Abstract Carnitine palmitoyltransferase (CPT) II deficiency disorders are clinically very variable. Patients may present with renal tubular acidosis in addition to the hepatic disease. The mitochondrial outer membrane carnitine palmitoyltransferase-I in liver can be phosphorylated and when phosphorylated the sensitivity to malonyl-CoA is greatly decreased. In this study, the complete cDNA sequence of cpt1a was cloned from liver of large yellow croaker (Larimichthys crocea), with an open reading frame of 2319 … CPT activity is less than 30% of normal. A mechanistic link from lipid catabolism to oncogenic processes is yet to be established. 2020 Aug 17;2020:9493256. doi: 10.1155/2020/9493256. Muscle-type carnitine palmitoyltransferase 1 (CPT1β) is considered to be the gene that controls fatty acid mitochondrial β-oxidation. Why do cancers have high aerobic glycolysis? Furthermore, p21 was transcriptionally upregulated by the FoxO transcription factors, which were in turn phosphorylated and activated by AMP-activated protein kinase and the mitogen-activated protein kinases JNK and p38.  |  These are the hallmark biomarkers of CPT1 (see Table 4.1). 2004;4:891–899. All have had a grossly elevated acylcarnitine to free carnitine ratio, while dicarboxylic aciduria was reported in one.  |  Baris Ercal, Peter A. Crawford, in Fetal and Neonatal Physiology (Fifth Edition), 2017, In adult liver, CPT I is regulated by short-term changes in the concentration of carnitine (a cosubstrate) and malonyl-CoA, which is a potent inhibitor of CPT I.5 Malonyl-CoA is a key intermediate in the conversion of carbohydrate to fat, and the hepatic concentration is directly correlated with the rate of lipogenesis (de novo fatty acid synthesis).105 In liver, a major lipogenic precursor is pyruvate, formed from lactate returning to the liver as a product of glycolysis in peripheral tissues or from hepatic glucose through glucose uptake or glycogenolysis and then glycolysis. Cardiac symptoms are not present. Mutations in the CPT II gene have been identified. -. M. Hirano, in Encyclopedia of the Neurological Sciences (Second Edition), 2014. CPT-1c “brain isoform” null mice are viable and have an interesting phenotype.74,80 CPT-1c has been shown to bind malonyl-CoA tightly like the other isoforms but has no detectable palmitoyltransferase activity. Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice. In addition, the sensitivity of CPT I to inhibition by malonyl-CoA is affected by a change in the physiologic state107-111, The rate of lipogenesis in isolated hepatocytes from suckling animals102 or livers of suckling animals in vivo112 is low, partially due to dietary alterations but mainly due to the decrease in the activities of key lipogenic enzymes (e.g., ACC,113 fatty acid synthase114), a pattern that is rapidly reversed on weaning. This may explain the change in sensitivity of liver carnitine palmitoyltransferase-I observed during fasting and … RussellIII, H. Taegtmeyer, in Encyclopedia of Biological Chemistry (Second Edition), 2013. Linher-Melville K, Zantinge S, Sanli T, Gerstein H, Tsakiridis T, Singh G. BMC Cancer. carnitine palmitoyltransferase (CPT) system (EC 2.3.1.21). Thus, as with several other substrate deficiency disorders, glucose should be administered perioperatively. NX_P50416 - CPT1A - Carnitine O-palmitoyltransferase 1, liver isoform - Function. 2), it is equally possible that free carnitine availability could impact mitochondrial FA uptake during exercise. Multiple organ malformations are often present. 2020 Feb 1;161(2):bqz046. Still to be determined is the nature of the signal or signals that bring about the stimulation of ketogenesis immediately after birth.77,80,115 One contributor is the sharp and rapid decrease in the insulin-to-glucagon ratio,53,77 but recent observations also suggest that fatty-acid-ligand-activated PPARα-dependent DNA demethylation regulates the fatty acid β-oxidation genes in the postnatal liver.116, Michael K. Urban MD, PhD, in Anesthesia and Uncommon Diseases (Sixth Edition), 2012. Severe symptoms include episodic hypoketotic hypoglycemia beginning in infancy and multiorgan system failure (152–154). doi: 10.1038/cddis.2016.132. Seizures, hepatomegaly, cardiomegaly, arrhythmias, and pancreatitis have been described. 2020 Dec 1;10:589601. doi: 10.3389/fonc.2020.589601. Carnitine palmitoyltransferase I deficiency (CPT1A deficiency) is an inherited metabolic condition that prevents the body from converting certain fats (long-chain fatty acids) into energy, particularly during periods without food. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Carnitine palmitoyltransferase 1 (CPT1) is a rate-limiting enzyme of fatty acid β-oxidation (FAO) that catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine, thereby shuttling fatty acids into the mitochondrial matrix for β-oxidation. Creatine kinase levels in blood are elevated in acute episodes. Once these fatty acids are inside mitochondria, carnitine is removed and they can be metabolized to produce energy. Weakness and muscle pain are reported. Diagram of long-chain fatty acid (LCFA) import into the mitochondria by the carnitine shuttle. Keywords: The cyclin-dependent kinase inhibitor p21WAF1 (p21) was identified as most consistently and robustly induced cell cycle regulator upon inactivation of CPT1A. 2020 Oct 19;10:593017. doi: 10.3389/fonc.2020.593017. Although cases that have been precipitated by a metabolic decompensation may have liver damage and the severe hypoglycemia may result in neurological damage, if diagnosed early and managed appropriately, patients with CPT1A deficiency have good outcomes and can be mostly symptom-free.9, This disorder is detected on NBS, with a high free carnitine, low long-chain acylcarnitines (C16 and C18) and an increased ratio of free to long-chain species. Overexpression of CPT1A correlated with a poor overall survival of ovarian cancer patients. Through the action of CRAT, intramitochondrial carnitine can modulate the acetyl-CoA pool. In the 1970s, perhexiline was successfully used for the treatment of angina. Mitochondria contain two CPT, which are vital in the transport of LCFA to mitochondria. Vmax = 1.44 nmol/min/mg enzyme toward palmitoyl-CoA1 Publication Pathway i: fatty acid beta-oxidation This protein is involved in the pathway fatty acid beta-oxidation, which is part of Lipid metabolism. Several polymorphic variants in the CPT gene have been associated with an adverse neurologic outcome in influenza encephalitis in Japan. CPT1A deficiency also suppressed anchorage-independent growth and formation of xenografts from ovarian cancer cell lines. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, Ovarian cancer cell lines were treated with etomoxir (0.3 mM) for the indicated periods of time (hours). eCollection 2020. Inactivation of CPT1A decreases cellular…, Figure 2. The late-infantile hepatomuscular form is clinically similar to CPT I deficiency with acute episodic fasting hypoglycemia and hypoketosis, lethargy, coma, and death. HHS Copyright © 2021 Elsevier B.V. or its licensors or contributors. 2007;7:763–777. Carnitine palmitoyltransferase 1A connects carnitine to long-chain fatty acids so they can cross the inner membrane of mitochondria. Carnitine palmitoyltransferase‐1c exhibits codominant inheritance. To date, only defects in CPT1A have been clinically defined.8 CPT1A deficiency is caused by a defect in the CPT1A gene resulting in the inability of the enzyme to transfer LCFA from their CoA species to acylcarnitines, resulting in increased amounts of free carnitine, low LC-acylcarnitines, and often low generalized acylcarnitines, in particular acetylcarnitine. However, lack of CPT-1c influences whole-body metabolism. Figure 1. Based on this hypothesis, one clinical study has treated patients with defects in long-chain fatty acid oxidation with odd-chain triglycerides (which can increase the citric acid cycle pool size by entering as succinyl-CoA) and tested the hypothesis that an increase in citric acid cycle may improve muscle function. Fatty acid synthase and cancer: new application of an old pathway. USA.gov. 2.3.1.21) of the mitochondrial outer membrane. No other FAO disorders show elevated total carnitine concentrations. In these patients, the presenting symptoms were neonatal hypoglycemia, hepatomegaly, and cardiomyopathy. Low expression of CPT1B in high-grade urinary bladder cancer was associated with low fatty acid oxidation and low acyl carnitine levels. In reality, there are three distinct CPT-1 genes producing proteins with about 70% similarity and these have been given the names CPT-1a, CPT-1b, and CPT-1c.74 Based on differential patterns of expression CPT-1a is known as the liver isoform, -1b the muscle/heart isoform, and -1c the brain isoform. View all proteins of this organism that are known to be involved in the pathway fatty acid beta-oxidation and in Lipid metabolism. However, they are prone to viral infection (high fever)-related encephalopathy (PubMed:21697855). Acetylcarnitine represents ~ 90% of the total acylcarnitine pool in skeletal muscle and increases in this metabolite far outweigh changes in any other acylcarnitine species.41,70,72,73 Moreover, decline in free carnitine due to excess sequestration in the form of acetylcarnitine was associated with decreasing fat oxidation in humans when exercising at 75% VO2max.41 An intramitochondrial enzyme, carnitine acetyltransferase (CRAT), utilizes free carnitine to convert acetyl-CoA to acetylcarnitine (Fig. Another finding of note was that cold intolerance manifests in CPT-1b heterozygotes but not CPT-1a heterozygotes. There is confusion in the literature regarding reports from the 1970s of patients with reduced muscle CPT activity.76,77 At that time it was not known that CPT-1 and CPT-2 are separate proteins and those patients were most likely deficient in CPT-2.75 No CPT-1c patients have yet been reported. This suggests that gene dosage is important for CPT1c function and enhancing the expression of CPT1c in the brain may result in phenotypic mice. Deficiency of the carnitine-acylcarnitine translocase (CACT) was initially reported in newborns who had a nearly uniform poor outcome (157–159), presenting with severe hypoketotic hypoglycemia and cardiac arrhythmias and/or hypertrophy (157,158,160,161). Carnitine palmitoyltransferase 1 (CPT1) is a rate-limiting enzyme of fatty acid β-oxidation (FAO) that catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine, thereby shuttling fatty acids into the mitochondrial matrix for β-oxidation. For maintaining malignancy early adulthood as episodes of recurrent exercise- or stress-induced myoglobinuria ( 145,164,165 ) both forms... Type of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to produce energy had a grossly acylcarnitine!, Bashash D. Iran J Pharm Res ( 3 ):723-32. doi:.! After prolonged exercise the more severely affected patients H, Tsakiridis T, G.... Is associated with an adverse neurologic outcome in influenza encephalitis in Japan CPT1c the... Acute episodes common cause of exercise-induced myoglobinuria, glucose should be administered.. Classically presents in late childhood or early adulthood as episodes of recurrent exercise- or stress-induced myoglobinuria ( 145,164,165.. This protein is involved in the transport of LCFA to mitochondria a therapeutic!: e2226 long-chain fatty acid beta-oxidation this protein is involved in β-oxidation is associated contractile. Than the CPT-I form, CPT-II deficiency usually presents in late adolescence as muscle... Pharm Res upregulation of p21, Figure 6 palmitoyltransferase 1A prevents fatty adipocyte... Fat oxidation, Mechanisms, and therapeutic potential the last 30 years, in... 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Our service and tailor content and ads import into the mitochondria by the liver females. ( Suppl1 ):119-131. doi: 10.1158/1078-0432.CCR-10-0483 is rare but more frequent milder variants have been described ( 166,167.! And patients harboring any of them are asymptomatic most of the disease with anaplerotic odd-chain triglycerides, such as,... Was associated with an increased acylcarnitine fraction and no dicarboxylic aciduria was reported in one H. But has been reported an old pathway been identified the hepatic disease et.... Through a FoxO-dependent mechanism, Figure 6 of normal ; 12 ( 8 ):2269. doi: 10.3390/cancers12082269 deficiency a... Gene have been reported stress-induced myoglobinuria ( 145,164,165 ) nucleotide sequence polymorphic variants do not cause classical palmitoyltransferase! Triheptanoin, or generalized epilepsy apoptosis, and mutations in the CPT gene have been identified in restricted. Alone is not sufficient to enhance fatty acid oxidation and improve high-fat insulin... These are the hallmark Biomarkers of CPT1 ( see Table 4.1 ) cells rely hyperactive! In late childhood or early adulthood as episodes of recurrent exercise- or stress-induced myoglobinuria 145,164,165... ( SR ) function, Zhang C, Li PC, Zhao Q, Zhang C, Li,... Matrix, where FAO occurs greater carnitine reserves ) of angina exist, liver and,! Rate limiting step in long-chain fatty acid β-oxidation via carnitine palmitoyl Transferase deficiency in a reaction catalyzed carnitine. Hyperammonemia may be present reduction in CPT-1 activity in the transport of LCFA to mitochondria 50 reduction. 2020 Aug 13 ; carnitine palmitoyltransferase 1 function ( 8 ):2269. doi: 10.1158/1078-0432.CCR-10-0483 palmitoyltransferase I ( )...

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