Adipose Triglyceride Lipase Is a Major Hepatic Lipase That Regulates Triacylglycerol Turnover and Fatty Acid Signaling and Partitioning

Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108-1038, USA.
Hepatology (Impact Factor: 11.06). 01/2011; 53(1):116-26. DOI: 10.1002/hep.24006
Source: PubMed


Despite advances in our understanding of the ways in which nutrient oversupply and triacylglycerol (TAG) anabolism contribute to hepatic steatosis, little is known about the lipases responsible for regulating hepatic TAG turnover. Recent studies have identified adipose triglyceride lipase (ATGL) as a major lipase in adipose tissue, although its role in the liver is largely unknown. Thus, we tested the contribution of ATGL to hepatic lipid metabolism and signaling. Adenovirus-mediated knockdown of hepatic ATGL resulted in steatosis in mice and decreased hydrolysis of TAG in primary hepatocyte cultures and in vitro assays. In addition to altering TAG hydrolysis, ATGL was shown to play a significant role in partitioning hydrolyzed fatty acids between metabolic pathways. Although ATGL gain and loss of function did not alter hepatic TAG secretion, fatty acid oxidation was increased by ATGL overexpression and decreased by ATGL knockdown. The effects on fatty acid oxidation coincided with decreased expression of peroxisome proliferator-activated receptor α (PPAR-α) and its target genes in mice with suppressed hepatic ATGL expression. However, PPAR-α agonism was unable to normalize the effects of ATGL knockdown on PPAR-α target gene expression, and this suggests that ATGL influences PPAR-α activity independently of ligand-induced activation. CONCLUSION: Taken together, these data show that ATGL is a major hepatic TAG lipase that plays an integral role in fatty acid partitioning and signaling to control energy metabolism.

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Available from: Andrew S Greenberg, Dec 20, 2013
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    • "Both, mutated ATGL or CGI-58 alleles promote neutral lipid storage disease (NLSD) characterized by TG accumulation in multiple tissues [3] including the liver. In mice, down-regulation or absence of ATGL or CGI-58 in the liver provokes marked hepatic fat accumulation [4] [5] [6]. Upon fasting, hepatic TG levels sharply increase due to enhanced TG mobilization from AT and increased fatty acid (FA) flow to the liver. "
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    ABSTRACT: Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, western blotting and ELISA. Impaired AT-derived FA supply upon fasting of CGI-58ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH-translocation. This severely reduced the expression of respective target genes such as the ATGL-inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 02/2015; 15(2). DOI:10.1016/j.jhep.2015.02.035 · 11.34 Impact Factor
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    • "In addition, circadian transcription of genes encoding acyl-CoA thioesterases may lead to rhythmic changes in the intracellular level of fatty acid ligands [44]. Other potential mechanisms for PPARa activation during fasting include induction of co-activator proteins such as PGC1a [42], and intracellular generation of PPARa ligands via lipolysis of locally stored triglycerides [45] [46]. "
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    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.02.002
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    • "PPAR family is also involved in the regulation of inflammation and energy homeostasis [38]. Among them, PPARα directly governs the triglyceride hydrolysis pathway in the liver [39]. CES3 and MGLL are induced in mouse hepatocytes by short-term treatment with PPARα agonist [40], but the present result showed down-regulation of CES3 in spite of up-regulation of PPAR signaling pathway. "
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