Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning

Ong, Kuok Teong; Mashek, Mara T.; Bu, So Young; Greenberg, Andrew S.; Mashek, Douglas G.

doi:10.1002/hep.24006

Cited by 296 publications

(320 citation statements)

References 45 publications

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“…In the liver, the rate-controlling step in triglyceride breakdown is catalyzed by adipose triglyceride lipase (ATGL). 25,26 As previously shown for adipocytes, 27 insulin decreased ATGL expression in hepatocytes both at low (10 mM) or high (25 mM) glucose concentration (Figure 4a). Unexpectedly, PGE 2 also decreased ATGL expression.…”

Section: Pge 2 -Dependent Inhibition Of Lipolysis and Mitochondrial Bsupporting

confidence: 79%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

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Section: Pge 2 -Dependent Inhibition Of Lipolysis and Mitochondrial Bsupporting

confidence: 79%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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“…The present study clearly showed that three fibrates, fenofibrate, bezafibrate, and clofibric acid, reduced the hepatic concentration of TAG in dose-and time-dependent manners, although conflicting results appear in the literature concerning the effects of fenofibrate on hepatic TAG content (11,24). In the current study, fenofibrate behaved as the most powerful hepatic TAG suppressor, while clofibric acid was the least potent.…”

Section: Discussionsupporting

confidence: 41%

“…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: 96%

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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“…Thus, hepatic depletion of adipose triglyceride lipase (ATGL) in mice leads to severe liver steatosis (Ong et al 2011). Decreased activity of ATGL in the liver of IR patients has also been associated with development of NAFLD (Kato et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL K/K mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4CTh17C cells. Consistent with increased inflammation, livers from HL K/K mice had augmented activation of the stress SAPK/JNK-and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL K/K and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL K/K mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK-and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.

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Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning

Cited by 296 publications

References 45 publications

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

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

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

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