The Peroxisome Proliferator-activated Receptor α (PPARα) Regulates Bile Acid Biosynthesis

Hunt, Mary C.; Yang, Yizeng; Eggertsen, Gösta; Carneheim, C.; Gåfvels, Mats; Einarsson, Curt; Alexson, Stefan E.H.

doi:10.1074/jbc.m002782200

Cited by 148 publications

(110 citation statements)

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“…This conclusion is further supported by the competition experiment carried out, which showed that addition of a small amount of recombinant PTE-2 to peroxisomes severely suppresses the activity of BAAT, presumably due to consumption of the substrate CDCA-CoA. PPAR␣ has been established as a key regulator of lipid metabolism, but was also shown to be involved in regulation of bile acid metabolism (38), thus connecting the pathways of bile acid and fatty acid metabolism. Up-regulation of PTE-2 by WY-14,643, together with the PTE-2-mediated suppression of bile acid conjugation with taurine in vitro, could imply that PPAR␣ is also involved in regulating bile acid amidation.…”

Section: Pte-2 Is a Ppar␣ Target Gene That May Regulate Bile Acidsupporting

confidence: 57%

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Characterization of an Acyl-CoA Thioesterase That Functions as a Major Regulator of Peroxisomal Lipid Metabolism

Hunt

Solaas

Kase

et al. 2002

Journal of Biological Chemistry

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144

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Peroxisomes function in ␤-oxidation of very long and long-chain fatty acids, dicarboxylic fatty acids, bile acid intermediates, prostaglandins, leukotrienes, thromboxanes, pristanic acid, and xenobiotic carboxylic acids. These lipids are mainly chain-shortened for excretion as the carboxylic acids or transported to mitochondria for further metabolism. Several of these carboxylic acids are slowly oxidized and may therefore sequester coenzyme A (CoASH). To prevent CoASH sequestration and to facilitate excretion of chain-shortened carboxylic acids, acyl-CoA thioesterases, which catalyze the hydrolysis of acyl-CoAs to the free acid and CoASH, may play important roles. Here we have cloned and characterized a peroxisomal acyl-CoA thioesterase from mouse, named PTE-2 (peroxisomal acyl-CoA thioesterase 2). PTE-2 is ubiquitously expressed and induced at mRNA level by treatment with the peroxisome proliferator WY-14,643 and fasting. Induction seen by these treatments was dependent on the peroxisome proliferator-activated receptor ␣. Recombinant PTE-2 showed a broad chain length specificity with acyl-CoAs from short-and medium-, to long-chain acyl-CoAs, and other substrates including trihydroxycoprostanoyl-CoA, hydroxymethylglutaryl-CoA, and branched chain acyl-CoAs, all of which are present in peroxisomes. Highest activities were found with the CoA esters of primary bile acids choloyl-CoA and chenodeoxycholoyl-CoA as substrates. PTE-2 activity is inhibited by free CoASH, suggesting that intraperoxisomal free CoASH levels regulate the activity of this enzyme. The acyl-CoA specificity of recombinant PTE-2 closely resembles that of purified mouse liver peroxisomes, suggesting that PTE-2 is the major acyl-CoA thioesterase in peroxisomes. Addition of recombinant PTE-2 to incubations containing isolated mouse liver peroxisomes strongly inhibited bile acidCoA:amino acid N-acyltransferase activity, suggesting that this thioesterase can interfere with CoASH-dependent pathways. We propose that PTE-2 functions as a key regulator of peroxisomal lipid metabolism.Peroxisomes are cellular organelles present in all eukaryotic cells. They play an indispensable role in the metabolism of a variety of lipids including very long-chain fatty acids, dicarboxylic fatty acids, bile acids, prostaglandins, leukotrienes, thromboxanes, pristanic acid, and xenobiotic fatty acids (for review, see Refs. 1 and 2). The peroxisomal ␤-oxidation system contains two sets of enzymes, one of which is involved in the oxidation of branched chain fatty acids and intermediates in the hepatic bile acid biosynthetic pathway and consists of one or two branched-chain acyl-CoA oxidase(s), a D-specific bifunctional protein and the sterol carrier-like protein x (SCPx). The second pathway is involved in the oxidation of very long straight-chain fatty acids, CoA esters of prostaglandins, leukotrienes, and thromboxanes (prostanoids) and dicarboxylic acids. This system is composed of a straight-chain acyl-CoA oxidase, an L-specific bifunctional protein and straight-chain 3-ke...

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Section: Pte-2 Is a Ppar␣ Target Gene That May Regulate Bile Acidsupporting

confidence: 57%

“…The role of the PPAR␣ in the fasting-mediated induction of several genes has also been shown (7)(8)(9)(10)38). We examined the effect of fasting on PTE-2 mRNA levels in the PPAR␣-null mouse model, which resulted in a significant increase in PTE-2 mRNA in liver (Fig.…”

Section: Fig 3 Pte-2 Is a Peroxisomal Matrix Proteinmentioning

confidence: 99%

Characterization of an Acyl-CoA Thioesterase That Functions as a Major Regulator of Peroxisomal Lipid Metabolism

Hunt

Solaas

Kase

et al. 2002

Journal of Biological Chemistry

Self Cite

144

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“…Second, the murine and rat sterol 12␣-hydroxylase gene, a branch-point enzyme in the bile salt biosynthetic pathway that determines the ratio of cholic acid to CDCA, is transcriptionally activated through direct binding of PPAR␣ to an imperfect DR1 sequence in the promoter region. Accordingly, treatment of wild-type mice with WY14643 for 1 week resulted in an increased relative amount of CA, an effect that was abolished in PPAR␣ null mice (43). Third, the inducing effects of PPAR␣ ligands on target genes encoding enzymes of fatty acid ␤-oxidation appear to be antagonized in mice by concomitant feeding of a bile salt-enriched diet, suggesting an influence of bile salts on PPAR␣-dependent gene regulation (44).…”

Section: Discussionmentioning

confidence: 99%

Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor α

Jung¹,

Fried²,

Kullak‐Ublick³

2002

Journal of Biological Chemistry

105

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The apical sodium-dependent bile salt transporter (ASBT/SLC10A2), also called the ileal bile acid transporter, mediates the intestinal absorption of bile salts. The efficiency of this transport process is a determinant of hepatic bile salt synthesis from cholesterol and of serum triglyceride levels. Our aim was to characterize the human ASBT gene promoter with respect to regulatory mechanisms that coordinately affect ASBT expression and hepatic lipid and bile salt metabolism. The minimal construct that confers full promoter activity contains three functional hepatocyte nuclear factor 1␣ (HNF1␣) recognition sites, explaining the dependence of ASBT gene expression upon HNF1␣. A nuclear receptor binding site arranged as a direct hexanucleotide repeat (DR1 motif) is localized ϳ1.6 kb upstream of the transcription initiation site. Constructs containing this element were transactivated by WY14643 and ciprofibrate, ligands of the peroxisome proliferator-activated receptor ␣ (PPAR␣), in Caco2 cells. The DR1 element was shown to bind the PPAR␣/9-cis-retinoic acid receptor heterodimer, and targeted mutagenesis of the DR1 motif abolished PPAR␣ responsiveness. Ciprofibrate treatment of SK-ChA cholangiocytes increased ASBT mRNA levels, suggesting a physiologic role for PPAR␣-mediated ASBT gene regulation. This study identifies PPAR␣ as a novel link between ileal bile salt absorption and hepatic lipid metabolism.

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“…Similar to Acot15, Acot2 is expressed in the liver, albeit at low levels, and is also expressed in cardiac and skeletal muscle (13)(14)(15)(16)(17), and is upregulated by fasting, streptozotocininduced diabetes, and peroxisome proliferator-activated receptor agonists ( 13,(15)(16)(17). Its major substrates are palmitoyl-CoA (PCoA) and myristoyl-CoA (MCoA) ( 18 ), which positions Acot2 as a potential regulator of longchain fatty acyl-CoA entry into FAO.…”

Section: Bioenergetics Analyses In Isolated Mitochondria and Hepatocytesmentioning

confidence: 99%

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver

Moffat

Bhatia

Nguyen

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Pathophysiological mechanisms that underlie metabolic dysfunction such as insulin resistance and nonalcoholic fatty liver disease are complex. A role for mitochondrial FA oxidation (FAO) as a driver of dysfunction has been postulated ( 1-3 ), yet the mechanistic link between cellular metabolic dysfunction and mitochondrial FAO remains poorly defi ned ( 2 ). Insight would be gained by a better understanding of FAO. In particular, the modulation of ␤ -oxidation substrates and intermediates by mechanisms within the mitochondria is poorly understood, but is of interest in the context of evidence suggesting that longchain fatty acyl-CoA esters can inhibit FAO ( 4-6 ).Acyl-CoA thioesterases (Acots) in mitochondria, by virtue of their major substrates (long-chain fatty acyl-CoAs) and hydrolase activity which generates FA anion and free CoASH, have the potential to modulate the levels of FAO substrates and intermediates, and consequently to modulate FAO. The Acots are classifi ed as type I or II based on catalytic domain structure, and localize to the cytosol, peroxisomes, and mitochondria. The mitochondrial Acots are Acot2 (mitochondrial matrix) ( 7 ), Acot9 (matrix) ( 8 ), Acot15/Them5 (matrix) ( 9 ), Acot11/Them1 (outside the matrix) ( 10 ), and Acot13/Them2 (outside the matrix) ( 11 ). All are type II thioesterases except for Acot2. The only matrix-localized Acot for which a functional role has been delineated is Acot15. Its germline deletion in mice Abstract Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxidative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from AdAcot2 mice, phosphorylating O 2 consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effl uxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our fi ndings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix. -Moffat, C., L. Bhatia, T. Nguyen, P. Lynch, M. Wang, D. Wang, O. R. Ilkayeva, X. Han, M. D. Hirschey, S. M. Claypool, and E. L. Seifert. Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in t...

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The Peroxisome Proliferator-activated Receptor α (PPARα) Regulates Bile Acid Biosynthesis

Cited by 148 publications

References 32 publications

Characterization of an Acyl-CoA Thioesterase That Functions as a Major Regulator of Peroxisomal Lipid Metabolism

Characterization of an Acyl-CoA Thioesterase That Functions as a Major Regulator of Peroxisomal Lipid Metabolism

Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor α

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver

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