Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor α activity

Sapiro, Jessica M.; Mashek, Mara T.; Greenberg, Andrew S.; Mashek, Douglas G.

doi:10.1194/jlr.m800614-jlr200

Cited by 82 publications

(86 citation statements)

References 43 publications

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“…These findings strongly suggest that ATGL is critically involved in the hepatocellular mobilization of fatty acids and fatty acid signaling (45). ATGL resides predominantly on cytosolic lipid droplets and on intracellular membranes (22).…”

Section: Discussionmentioning

confidence: 89%

“…ATGL overexpression enhances TAG hydrolysis, and the consequential release of fatty acids drives PPARa activity in rat hepatocytes (11,14,45); conversely, ATGL deficiency leads to down-regulation of PPARa target genes in the liver (11). These findings strongly suggest that ATGL is critically involved in the hepatocellular mobilization of fatty acids and fatty acid signaling (45).…”

Section: Discussionmentioning

confidence: 94%

“…One is that the fatty acids are transported by FABP to mitochondria, where they are exclusively utilized for b-oxidation. The other is that the released fatty acids are similarly transported to the nucleus, where they activate PPARa as its ligand (45), activation of the transcription factor that relays further stimulation of fatty acid uptake (FAT/CD36), fatty acid trafficking (FABP1), fatty acid activation (ACSL1, 3), mitochondrial b-oxidation (CPT1a, MCAD, LCAD) and peroxisomal b-oxidation (Acox1), and ATGL as well. Thus, ATGL may further expand this positive feedback loop interplaying among PPARa, ATGL, and b-oxidation system in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

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

Karahashi¹,

Hoshina²,

Yamazaki³

et al. 2013

J Pharmacol Sci

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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.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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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

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“…FAs located in the sn-1 position of TG are both saturated (ϳ70%) and unsaturated (ϳ30%), and lipolysis of TG-rich lipoproteins by lipoprotein lipase can provide FA ligand for PPAR␣ activation in endothelial cells (85) and macrophages (11). Furthermore, ATGL overexpression enhances lipolysis and drives PPAR␣ activity in rat hepatocytes (64), and ATGL overexpression in adipocytes increases the expression of PPAR target genes (1). Also, PPAR␥ agonism increases adipose tissue lipolysis, mitochondrial biogenesis, and FA oxidation (50,81).…”

Section: Atgl and Mitochondrial Biogenesismentioning

confidence: 99%

Triacylglycerol lipases and metabolic control: implications for health and disease

Watt

Spriet

2010

American Journal of Physiology-Endocrinology and Metabolism

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Watt MJ, Spriet LL. Triacylglycerol lipases and metabolic control: implications for health and disease. Am J Physiol Endocrinol Metab 299: E162-E168, 2010. First published January 12, 2010; doi:10.1152/ajpendo.00698.2009.-Fatty acids derived from the hydrolysis of adipose tissue and skeletal muscle triacylglycerol (TG) are an important energy substrate at rest and during physical activity. This review outlines the identification of the new TG lipase, adipose triglyceride lipase, the current understanding of how cellular TG lipases are regulated, and the implications for understanding the integrated control of TG lipolysis. Furthermore, this review outlines recent advances that propose a "revised" role for TG lipases in cellular function, metabolic homeostasis, and disease prevention. fatty acid; metabolism; adipose; skeletal muscle TRIACYLGLYCEROLS (TG) are stored within discrete cytosolic lipid droplets within most tissues. Contrary to the common misconception in the literature that the TG pool is "inert," these droplets are highly dynamic, and the TG within is highly labile. The overall TG content within these droplets is ultimately dependent on the balance between the rates of TG hydrolysis and fatty acid uptake, oxidation, and storage. The fatty acids derived from TG breakdown participate in a variety of cellular processes, including membrane biosynthesis, signal transduction, and, most critically for this review, ATP production after ␤-oxidation. From a systemic viewpoint, fatty acids can be derived from both intracellular and extracellular sources, and with the exception of adipose tissue, the latter is most prevalent due to limited intracellular stores. Under postprandial conditions, ϳ30% of total energy expenditure is reliant on fatty acids derived from adipose TG hydrolysis, and this becomes quantitatively more important with extended fasting or exercise. In cases of caloric surplus leading to obesity, elevated circulating fatty acids may contribute to the accumulation of intramyocellular and hepatic lipids, which are associated with secondary metabolic complications such as insulin resistance (77). Therefore, the liberation of fatty acids from adipocyte TG and release into the systemic circulation is under most conditions the first point of control in the regulation of fatty acid metabolism, and accordingly, tight control of adipocyte lipolysis is a critical mediator of whole body metabolic homeostasis. Similarly, an emerging body of evidence indicates that altering TG metabolism within ectopic tissues, such as liver and skeletal muscle, can influence local fatty acid metabolism with implications for obesity-related metabolic disorders.This review will first focus on the regulation of TG lipolysis and how the understanding of TG regulation has evolved since the discovery and partial characterization of adipose triglyceride lipase (ATGL) only 5 years ago. The review will then outline how changes in TG metabolism can influence adipocyte and skeletal muscle metabolism and summarize the recent evidence sug...

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“…Also intracellular fatty acids derived from de novo lipogenesis or hydrolysis of triacylglycerol (TAG) or phospholipid can activate these transcription factors. For example, recent evidence suggests that modulating specific pathways, such as de novo fatty acid synthesis or TAG hydrolysis, which supply intracellular fatty acids, regulates gene expression (12,13). Such evidence that different regulation of these transcription factors by fatty acid type (unsaturated versus saturated) or source (intracellular versus exogenous) implicates that certain proteins or enzymes that control cellular uptake or trafficking of fatty acids and their downstream metabolites could mediate their effects on gene expression.…”

mentioning

confidence: 99%

Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor α activity

Cited by 82 publications

References 43 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

Triacylglycerol lipases and metabolic control: implications for health and disease

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

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