The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter

Dongol, Bikesh; Shah, Yatrik M.; Kim, Insook; Gonzalez, Frank J.; Hunt, Mary C.

doi:10.1194/jlr.m700119-jlr200

Cited by 68 publications

(56 citation statements)

References 37 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since it is difficult to provide definite experimental proof that the induction of ATGL by fibrates working in the liver is quantitatively mediated through the activation of PPARa in vivo, the present study employed an approach to estimate the in vivo potency of the three fibrates by the determination of the increase in mRNA abundance of the Acot1 gene. Acot1 encodes long-chain Acot1 (42,43), which was found to be one of two different peroxisome proliferator-inducible palmitoyl-CoA hydrolases in rat liver cytosol and is not a constitutive enzyme in the liver (44). Moreover, Acot1 has been demonstrated to be regulated by fibrate treatment through the action of PPARa in vivo (43).…”

Section: Discussionmentioning

confidence: 99%

“…Acot1 encodes long-chain Acot1 (42,43), which was found to be one of two different peroxisome proliferator-inducible palmitoyl-CoA hydrolases in rat liver cytosol and is not a constitutive enzyme in the liver (44). Moreover, Acot1 has been demonstrated to be regulated by fibrate treatment through the action of PPARa in vivo (43). The finding may indicate that Acot1 can be used as a likely outcome of activated PPARa working functionally in vivo in the liver.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Karahashi¹,

Hoshina²,

Yamazaki³

et al. 2013

J Pharmacol Sci

View full text Add to dashboard Cite

Abstract. Hepatic triacylglycerol (TAG) homeostasis is maintained by carefully regulated balance between its synthesis and disposal. Impairment in this balance causes steatosis. The aims of this study were i) to uncover whether fibrates control TAG concentration through the action of adipose triglyceride lipase (ATGL) and ii) to compare the potency of the effects on ATGL expression and TAG concentration among fenofibrate, bezafibrate, and clofibric acid in the liver of rats. Treatments of rats with the three fibrates induced ATGL and concomitantly decreased hepatic TAG concentration. The upregulation of ATGL was likely mediated through the activation of peroxisome proliferator-activated receptor a. Fibrates also expanded capacity of fatty acid b-oxidation. Importantly, three fibric acids (fenofibric, bezafibric, and clofibric acids) that are active metabolites formed in the liver exhibited almost the same potency to elevate ATGL expression in vivo, despite the fact that there were considerable differences in this regard among fenofibrate, bezafibrate, and clofibric acid when compared on the basis of their dosage. These results suggest that ATGL represents a potential therapeutic target for ameliorating hepatic steatosis and that fibric acids are promising agents to ameliorate and/or protect against hepatic steatosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Karahashi¹,

Hoshina²,

Yamazaki³

et al. 2013

J Pharmacol Sci

View full text Add to dashboard Cite

show abstract

“…Moreover, the mechanisms underlying the induction of ACOT7 in the heart and skeletal muscle are also unclear, while the induction of ACOT1 and ACOT2 seems to be mediated by PPAR alpha. 7,25,26) We have pointed out beneficial aspects of ACOT upregulation with respect to alleviation of lipotoxicity and insulin resistance. However, it has not been determined whether the lipotoxic conditions detrimental to obese animals are associated with maladaptation of ACOT expression, because our dietinduced obesity model fed a high-fat diet, but not a Western diet, 21) showed no apparent metabolic problems.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, acyl-CoA synthesized at the expense of ATP utilization would be repeatedly hydrolyzed, leading to the development of a futile energy-wasting cycle. 8,20,21) Moreover, some of the fatty acids released by acyl-CoA hydrolysis via ACOT1 may reach and activate a nuclear receptor, peroxisome proliferator-activated receptor alpha (PPAR alpha), which in turn stimulates the expression of genes related to lipid catabolism, including ACOT itself [24][25][26] and uncoupling protein 3 (UCP3) 27) to form a positive feedback loop. 8) On the other hand, in the mitochondrial matrix, acyl-CoA transported via CPT is subjected to beta-oxidation.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Fatty Acyl-CoA Thioesterases in the Heart and Skeletal Muscle of Rats Fed a High-Fat Diet

Fujita

Momose

Ohtomo

et al. 2011

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Over the past few decades, the prevalence of overweight and obesity has increased markedly worldwide, along with the adoption of westernized lifestyles characterized by excessive energy intake and a lack of physical activity. Consequently, obesity and a cluster of obesity-related comorbidities often referred to as the metabolic syndrome have become a serious public health problem and a major risk factor for the development of severe diseases such as cardiovascular disease. 1) Obesity is strongly associated with insulin resistance, in which elevation of circulating fatty acids results in increased fatty acid availability that exceeds the fat disposal capacity of cells, which decreases insulin-stimulated glucose oxidation in muscles and subsequently leads to contractile dysfunction of the heart. 2) The precise mechanisms underlying these "lipotoxic" consequences remain incompletely defined, but it is currently accepted that excessive fatty acid uptake into cells leads to the accumulation of proinflammatory lipid metabolites such as fatty acyl-CoA, diacylglycerol and ceramide. These metabolites stimulate stress-activated kinases, which interfere with insulin signaling. 2,3) It is also becoming clear that fatty acid beta-oxidation is increased in the insulin-resistant heart and oxidative skeletal muscle, and that mitochondrial overload and incomplete oxidation of fatty acids contribute to the impairment of insulin sensitivity. 2,4) Under these conditions, enhanced beta-oxidation, which is not accompanied by appropriate upregulation of the tricarboxylic acid (TCA) cycle or electron transport chain (ETC) activity, fails to oxidize fatty acids completely to CO 2 and deposits incomplete fat catabolites along with diminished levels of TCA cycle intermediates. These stressful environments created within mitochondria are thought to exacerbate cellular insulin resistance by enhanced oxidative stress, for example. 4) However, acyl-CoA thioesterase (ACOT) exists within the mitochondrial matrix of mammalian cells 5) and its expression is expected to be upregulated in response to fatty acid overload, as demonstrated in diabetic and fasted animals. 6,7) ACOT comprises a group of enzymes that are localized in multiple compartments in cells and catalyze the hydrolysis of long-chain acyl-CoA thioesters to free fatty acids and CoA-SH. For example, ACOT1 (formerly known as CTE-I or ACH2) and ACOT7a (CTE-II, BACH or ACT) are localized in the cytosol while ACOT2 (MTE-I or ARTISt) and ACOT7b (MTE-II or LACH1) are present in mitochondria. [8][9][10] These catalytic properties of ACOT mean that it is capable of lowering the increased levels of acyl-CoA imported by carnitine palmitoyltransferase (CPT) across the mitochondrial membranes from the cytosol. Accordingly, ACOT could counteract the enhanced beta-oxidation and reduce the mitochondrial stress caused by the imbalance between beta-oxidation and TCA cycle/ETC activity during fatty acid overload. Moreover, the ACOT isoforms present in the cytosol could scavenge surplus acyl-CoA to prev...

show abstract

“…The characteristics of the primary human hepatocytes and their upregulated by K-877 treatment are involved in carbohydrate and lipid metabolism (Table 3), of which Cyp4a31 19) , Pdk4 12) , Cidec 20) , Acot1 21) , Acot2 22) , Acot3 23) , Slc27a1 (FATP1) 13) , Vnn1 24,25) and Aqp3 26) have been reported to be PPARs target genes. On the other hand, K-877 treatment reduced the expression of phase enzymes and xenobiotic transporters, such as the Slco1a4, Sult1a1, Slc22a7 and Cyp2c54 genes 27) ( Table 4).…”

Section: K-877 Regulates Fatty Acid Metabolic Genes In Primary Human mentioning

confidence: 99%

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Raza-Iqbal

Tanaka

Anai

et al. 2015

J Atheroscler Thromb

Self Cite

View full text Add to dashboard Cite

Aim: Selective PPAR modulators (SPPARM ) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARM K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. Methods: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARM on the liver gene expression. Results: Consequently, a cell-based transactivation assay showed that K-877 activates PPAR with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid -oxidative genes in human hepatocytes and the mouse liver. Almost all genes up-or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly

show abstract

The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter

Cited by 68 publications

References 37 publications

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Upregulation of Fatty Acyl-CoA Thioesterases in the Heart and Skeletal Muscle of Rats Fed a High-Fat Diet

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Contact Info

Product

Resources

About