Participation of Two Members of the Very Long-chain Acyl-CoA Synthetase Family in Bile Acid Synthesis and Recycling

Mihalik, Stephanie J.; Steinberg, Steven J.; Pei, Zhengtong; Park, Joseph; Kim, Do G.; Heinzer, Ann K.; Dacremont, Georges; Wanders, Ronald J. A.; Cuebas, Dean; Smith, Kirby D.; Watkins, Paul A.

doi:10.1074/jbc.m203295200

Cited by 101 publications

(101 citation statements)

References 32 publications

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“…32 The persistence of conjugation defects in P36 PEX2 mutants may reflect delayed maturation of the peroxisomal/cytosolic-located bile acid-CoA:amino acid Nacyltransferase enzyme (BAAT), which conjugates bile acids to taurine or glycine and increases around weaning in control mice, 32 but other conjugation enzymes may also have been affected. 33,34 Interestingly, patients with BAAT gene mutations also accumulated unconjugated bile acids in plasma. 35 Initial studies in which PEX2 mutants were fed conjugated bile acids, rather than unconjugated ones, have not shown any difference in growth or survival (P. Faust, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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The marked deficiency of peroxisomal organelle assembly in the PEX2 ؊/؊ mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state. PEX2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36. We confirmed the expected reduction of mature C24 bile acids, accumulation of C27-bile acid intermediates, and low total bile acid level in liver and bile from these mutant mice. Treating the PEX2 ؊/؊ mice with bile acids prolonged postnatal survival, alleviated intrahepatic cholestasis and intestinal malabsorption, reduced C27-bile acid intermediate production, and prevented older mutants from developing severe steatohepatitis. However, this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver. Both untreated and bile acid-fed PEX2 ؊/؊ mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters. Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX2 mutants, indicating a generalized defect in bile acid conjugation. Conclusion: Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice, and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease. (HEPATOLOGY 2007;45:982-997.)

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Section: Discussionmentioning

confidence: 99%

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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“…It should be noted that FAs may not only be the sole substrate for some isoforms. For example, FATP5 preferentially activates bile acids and FATP2 activates both long-chain FA and 3α, 7α, 12α-trihydroxy-5β-cholestanoate [9]. The ACSBG isoforms prefer long-chain FA [10,11].…”

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confidence: 99%

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

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Thirteen homologous proteins comprise the long-chain acyl-CoA synthetase (ACSL), fatty acid transport protein (FATP), and bubblegum (ACSBG) subfamilies that activate long-chain and verylong-chain fatty acids to form acyl-CoAs. Gain-and loss-of-function studies show marked differences in the ability of these enzymes to channel fatty acids into different pathways of complex lipid synthesis. Further, the ability of the ACSLs and FATPs to enhance cellular FA uptake does not always require these proteins to be present on the plasma membrane; instead, FA uptake can be increased by enhancing its conversion to acyl-CoA and its metabolism in downstream pathways. Since altered fatty acid metabolism is a hallmark of numerous metabolic diseases and pathological conditions, the ACSL, FATP and ACSBG isoforms are likely to play important roles in disease etiology. A family of acyl-CoA synthetases activates intracellular long-chain fatty acidsBefore a fatty acid (FA) from an exogenous or endogenous source can enter any metabolic pathway with the exception of eicosanoid metabolism, it must first be activated to form an acyl-CoA. This activation step is catalyzed by acyl-CoA synthetase (ACS) via a two-step reaction: 1) the formation of an intermediate fatty acyl-AMP with the release of pyrophosphate, and 2) the formation of a fatty acyl-CoA with the release of AMP.The ACS family is comprised of at least 25 members [1]. Although overlap exists, ACS family members are broadly classified by their substrate specificities for FAs of varying chain length. This review will focus on the three subfamilies of ACS enzymes that activate long-chain and/ or very-long-chain saturated and unsaturated FAs, long-chain ACSs (ACSL), very-long-chain ACSs (FATP), and bubblegum (ACSBG) isoforms [2].The ACSL, FATP and ACSBG families include multiple isoforms, each encoded by a separate gene (Tables 1, 2). Additionally, splice variants of ACSL isoforms have been identified in both humans and rodents [3]. ACS enzymes share significant amino acid sequence similarity, particularly in two highly conserved regions, a putative ATP-AMP signature motif for ATP binding and a motif for FA binding [4]. Despite these similarities, purified ACSL and FATP isoforms and their splice variants show distinct enzyme kinetics, differences in sensitivity to inhibitors ( Role of acyl-CoA synthetases in FA channelingThe existence of 13 ACSL, FATP and ACSBG isoforms that all activate long-chain FA has suggested that each has an independent role in channeling FA within cells. Unique roles for ACS isoforms were first identified in studies of Saccharomyces cerevisiae mutants that lacked the ACS isoforms Faa1 and Faa4, and were unable to use exogenously provided fatty acids [31]. Similarly, complementation studies of ACS-deficient E. coli showed that each of the 5 rat ACSL isoforms differs in its ability to channel FA into specific pathways like phospholipid synthesis and β-oxidation [32]. The ACSL and FATP isoforms also differ in their ability to complement FA uptake and a...

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“…In view of the data showing BAAT activity in cytosol/microsomes and peroxisomes, it has been hypothesized that two pathways for amidation of bile acids exist, one pathway in peroxisomes for the amidation of the denovo synthesized primary bile acids, cholic acid and chenodeoxycholic acid, and a second pathway in the cytosol for the re-amidation of deconjugated primary and secondary bile acids recycled back to the liver via the enterohepatic circulation. The human very long-chain acyl-CoA synthetase homolog 2 (VLCS), also known as BACS (bile acid-CoA synthetase), was shown to activate the primary bile acids cholate [140] and chenodeoxycholate, and also the secondary bile acids deoxycholate and lithocholate [141] in the cytosol, also suggesting two pathways of bile acid metabolism, with the cytosolic pathway being responsible for reactivation/reconjugation of recycled bile acids.…”

Section: Peroxisomes Contain a Bile-acid Conjugating Enzyme Catalyzinmentioning

confidence: 99%

Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism

Hunt

Alexson

2008

Progress in Lipid Research

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Participation of Two Members of the Very Long-chain Acyl-CoA Synthetase Family in Bile Acid Synthesis and Recycling

Cited by 101 publications

References 32 publications

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism

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