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Metabolic and tissue-specific regulation of acyl-CoA metabolism.

Ellis JM, Bowman CE, Wolfgang MJ - PLoS ONE (2015)

Bottom Line: We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner.Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue.Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Center for Metabolism and Obesity Research, Baltimore, Maryland 21205 United States of America.

ABSTRACT
Acyl-CoA formation initiates cellular fatty acid metabolism. Acyl-CoAs are generated by the ligation of a fatty acid to Coenzyme A mediated by a large family of acyl-CoA synthetases (ACS). Conversely, acyl-CoAs can be hydrolyzed by a family of acyl-CoA thioesterases (ACOT). Here, we have determined the transcriptional regulation of all ACS and ACOT enzymes across tissues and in response to metabolic perturbations. We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner. Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue. Doubling cytosolic acyl-CoA thioesterase activity failed to protect mice from diet-induced obesity, fatty liver or insulin resistance, however, overexpression of Acot7 in adipocytes rendered mice cold intolerant. Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

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Relative tissue distribution of the acyl-CoA synthetases.Percent distribution of each enzyme was determined by qPCR in relation to the sum of its expression across all conditions for the liver (Liv), heart (Hrt), kidney (Kid), gonadal white adipose (Gon), inguinal white adipose (Ing), soleus muscle (Sol), plantaris muscle (Plant), duodenum (Gut), whole brain (Brain), and brown adipose tissue (BAT), n = 20–45. Data represent mean percent ± SEM.
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pone.0116587.g003: Relative tissue distribution of the acyl-CoA synthetases.Percent distribution of each enzyme was determined by qPCR in relation to the sum of its expression across all conditions for the liver (Liv), heart (Hrt), kidney (Kid), gonadal white adipose (Gon), inguinal white adipose (Ing), soleus muscle (Sol), plantaris muscle (Plant), duodenum (Gut), whole brain (Brain), and brown adipose tissue (BAT), n = 20–45. Data represent mean percent ± SEM.

Mentions: To understand how these metabolic perturbations altered the enzymes that initially generate or hydrolyze acyl-CoAs, we profiled the mRNA abundance of the 15 identified mouse acyl-CoA thioesterases and 25 acyl-CoA synthetases by real time qPCR in the tissues and dietary manipulations described above. We could not distinguish between Acot9 and Acot10 due to a ~97% mRNA sequence identity, therefore this data is expressed as Acot9/10. Each of the ACOT and ACS enzymes is known to have distinct tissue-specific expression patterns [16–17]. Here, we represent the cross-tissue expression for each enzyme as the percentage relative to the sum of expression across all tissues. We find very diverse expression across tissues with some enzymes being expressed widely, such as Them4, Them5, Acsl4, and Acsf4; whereas other enzymes are highly expressed in one or two tissues, such as Acot3, Acot5, Acot11, Acot12, Acsm1, Acsm2, Acsm4, Acsl6, Fatp5, and Acsbg1 (Fig. 2 and Fig. 3). A majority of the ACS and ACOT enzymes are enriched in one or a few tissues as opposed to being expressed widely, and we postulate that this reflects the evolutionary diversification of these enzyme families in order to regulate acyl-CoA metabolism in a tissue-specific manner.


Metabolic and tissue-specific regulation of acyl-CoA metabolism.

Ellis JM, Bowman CE, Wolfgang MJ - PLoS ONE (2015)

Relative tissue distribution of the acyl-CoA synthetases.Percent distribution of each enzyme was determined by qPCR in relation to the sum of its expression across all conditions for the liver (Liv), heart (Hrt), kidney (Kid), gonadal white adipose (Gon), inguinal white adipose (Ing), soleus muscle (Sol), plantaris muscle (Plant), duodenum (Gut), whole brain (Brain), and brown adipose tissue (BAT), n = 20–45. Data represent mean percent ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356623&req=5

pone.0116587.g003: Relative tissue distribution of the acyl-CoA synthetases.Percent distribution of each enzyme was determined by qPCR in relation to the sum of its expression across all conditions for the liver (Liv), heart (Hrt), kidney (Kid), gonadal white adipose (Gon), inguinal white adipose (Ing), soleus muscle (Sol), plantaris muscle (Plant), duodenum (Gut), whole brain (Brain), and brown adipose tissue (BAT), n = 20–45. Data represent mean percent ± SEM.
Mentions: To understand how these metabolic perturbations altered the enzymes that initially generate or hydrolyze acyl-CoAs, we profiled the mRNA abundance of the 15 identified mouse acyl-CoA thioesterases and 25 acyl-CoA synthetases by real time qPCR in the tissues and dietary manipulations described above. We could not distinguish between Acot9 and Acot10 due to a ~97% mRNA sequence identity, therefore this data is expressed as Acot9/10. Each of the ACOT and ACS enzymes is known to have distinct tissue-specific expression patterns [16–17]. Here, we represent the cross-tissue expression for each enzyme as the percentage relative to the sum of expression across all tissues. We find very diverse expression across tissues with some enzymes being expressed widely, such as Them4, Them5, Acsl4, and Acsf4; whereas other enzymes are highly expressed in one or two tissues, such as Acot3, Acot5, Acot11, Acot12, Acsm1, Acsm2, Acsm4, Acsl6, Fatp5, and Acsbg1 (Fig. 2 and Fig. 3). A majority of the ACS and ACOT enzymes are enriched in one or a few tissues as opposed to being expressed widely, and we postulate that this reflects the evolutionary diversification of these enzyme families in order to regulate acyl-CoA metabolism in a tissue-specific manner.

Bottom Line: We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner.Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue.Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Center for Metabolism and Obesity Research, Baltimore, Maryland 21205 United States of America.

ABSTRACT
Acyl-CoA formation initiates cellular fatty acid metabolism. Acyl-CoAs are generated by the ligation of a fatty acid to Coenzyme A mediated by a large family of acyl-CoA synthetases (ACS). Conversely, acyl-CoAs can be hydrolyzed by a family of acyl-CoA thioesterases (ACOT). Here, we have determined the transcriptional regulation of all ACS and ACOT enzymes across tissues and in response to metabolic perturbations. We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner. Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue. Doubling cytosolic acyl-CoA thioesterase activity failed to protect mice from diet-induced obesity, fatty liver or insulin resistance, however, overexpression of Acot7 in adipocytes rendered mice cold intolerant. Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

Show MeSH
Related in: MedlinePlus