Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.

Feingold, Kenneth R.; Marshall, Maureen K.; Gulli, Rocco; Moser, Arthur H.; Grünfeld, Carl

doi:10.1161/01.atv.14.11.1866

Cited by 105 publications

(80 citation statements)

References 37 publications

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“…[25][26][27] Like LPS, these cytokines also inhibit cholesterol 7␣-hydroxylase in the liver and lipoprotein lipase activity in adipose tissue. 7,28 In the present study, IL-1 administration increased both SPT activity (50% to 80%) and mRNA levels (2-fold to 3-fold) in the liver of Syrian hamsters; however, TNF had no such effect on SPT activity or mRNA levels in intact animals. Conversely, treatment of HepG2 cells, a human hepatoma cell line, with TNF, IL-1, or IL-6 increased SPT mRNA levels by 2-fold to 3-fold.…”

Section: Discussioncontrasting

confidence: 50%

Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and Produce Lipoproteins Enriched in Ceramides and Sphingomyelin

Memon

Holleran

Moser

et al. 1998

ATVB

153

132

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Abstract-Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections.We studied the effects of endotoxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphingolipid content in Syrian hamsters. Administration of LPS induced a 2-fold increase in hepatic SPT activity. The increase in activity first occurred at 16 hours, peaked at 24 hours, and was sustained for at least 48 hours. Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at Ϸ0.3 g LPS/100 g body weight.LPS increased hepatic SPT mRNA levels 2-fold, suggesting that the increase in SPT activity was due to an increase in SPT mRNA. LPS treatment also produced 75% and 2.5-fold increases in hepatic sphingomyelin and ceramide synthesis, respectively. Many of the metabolic effects of LPS are mediated by cytokines. Interleukin 1 (IL-1), but not tumor necrosis factor, increased both SPT activity and mRNA levels in the liver of intact animals, whereas both IL-1 and tumor necrosis factor increased SPT mRNA levels in HepG2 cells. IL-1 produced a 3-fold increase in SPT mRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Increased hepatic fatty acid synthesis, as well as increased adipose tissue lipolysis, provides the fatty acid substrate for increased triglyceride production.3 High doses of LPS do not stimulate hepatic VLDL secretion 3 but inhibit the clearance of triglyceride-rich lipoproteins by decreasing lipoprotein lipase activity in heart, muscle, and adipose tissue and in postheparin plasma. In rodents, LPS treatment increases serum cholesterol levels; however, this effect is delayed in onset compared with the increase in serum triglyceride levels and is primarily accounted for by an increase in LDL cholesterol.4 LPS increases hepatic cholesterol synthesis and the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. 4Increased transcription of the HMG-CoA reductase gene leads to increased mRNA and protein levels, which account for the increase in hepatic HMG-CoA reductase activity. 5This effect of LPS on hepatic HMG-CoA reductase is specific, because mRNA levels of other important enzymes in cholesterol synthesis, such as HMG-CoA synthase, farnesyl pyrophosphate synthase, and squalene synthase, are not increased. 5,6 In addition, LPS decreases the activity and mRNA levels of cholesterol 7␣-hydroxylase, the rate-limiting enzyme in bile acid synthesis.7 A decrease in bile acid synthesis would increase the availability of cholesterol for lipoprotein production. Finally, LPS has minimal or no effect on LDL receptor protein or mRNA levels in the liver, the organ primarily responsible for LDL clearance. 4 These results suggest that the increased production of lipoproteins rather

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Section: Discussioncontrasting

confidence: 50%

Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and Produce Lipoproteins Enriched in Ceramides and Sphingomyelin

Memon

Holleran

Moser

et al. 1998

ATVB

153

132

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“…In mice, administration of TNF-a resulted in an acute increase of plasma TG and inhibition of TNF decreased LPS-induced TG elevation. 21,22 TNF administration to insulinopenic diabetic rats also increased serum triglycerides. 23,24 While in a phase I pharmacological study, continuously infused rH-TNF (recombinant human tumor necrosis factor) for 24 h was associated with significant decreases in serum cholesterol and HDL levels.…”

Section: There Is a Link Between Tnf-a And Dyslipidemiamentioning

confidence: 86%

TNF‐α, a potent lipid metabolism regulator

Chen

Xun

Chen³

et al. 2009

Cell Biochemistry & Function

190

120

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As a multifunctional cytokine, tumor necrosis factor alpha (TNF-a) exerts a series of biological actions in different cells, tissues, organs, and species and has been demonstrated to regulate and interfere with energy metabolism, especially lipid homeostasis. A large body of researches suggested that the effects of TNF-a on lipid metabolism mainly include five aspects: (1) suppresses free fatty acid (FFA) uptake and promotes lipogenesis; (2) induces lipolysis; (3) inhibits lipid-metabolism-related enzymes activity; (4) regulates cholesterol metabolism; (5) regulates other adipocyte-derived adipokines. The molecular mechanisms underlying these actions are complex and several signal transduction pathways might be involved. Regulation of metabolism-related gene expression at transcriptional and protein levels and impact on enzymes activity might be of importance. Identification and verification of these pathways might provide novel potential strategies and drug targets for dyslipidemia therapy. However, the inconsistent and even conflict conclusions on lipid profile drawn from human subjects after infliximab therapy poses the possibility that the effect of TNF-a on lipid metabolism might be more complicated than it appeared to be.

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“…8,10,14 On the other hand, LPL expression is downregulated by inflammatory cytokines in vitro and in vivo, 16 implicating the attenuated LPL-mediated FA supply. The present study has expanded the understating of regulated expression and significance of EL in the heart both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Lipase Modulates Pressure Overload–Induced Heart Failure Through Alternative Pathway for Fatty Acid Uptake

et al. 2013

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A lthough a number of therapeutic advances have been made for the treatment of heart failure (HF), the prevalence and mortality of HF continue to grow worldwide. To develop novel therapies for HF, there is still a need to achieve better understanding of cardiac function and pathophysiology of HF using appropriate animal models of HF. The heart is constantly undergoing contraction and relaxation events that require a large amount of energy. Under physiological conditions, nearly 70% of the energy substrate used for myocardial contraction is derived from fatty acid (FA) oxidation, and the remainder comes from glucose and lactate oxidation.1 Exogenous FAs are obtained from free FAs that circulate in association with albumin and from the hydrolysis of triglyceride-rich lipoproteins via the actions of lipoprotein lipase (LPL). 2 The majority of FAs acquired by normal hearts are derived from esterified FAs contained in triglycerides and phospholipids. 3 Endothelial lipase (EL) is a member of the triglyceride lipase family. 4,5 EL is mainly expressed in vascular endothelial cells, but to a lesser extent, in macrophages, hepatocytes, and myocytes, 6 although the functional significance of EL expression in these cell types has not been fully understood. EL has primarily phospholipase activity and relatively less triglyceride lipase activity, and exhibits preferential substrate specificity for phospholipids on high-density lipoproteins (HDL). In other words, EL can release free FAs for energy source by hydrolyzing HDL phospholipids.7 Upregulation of EL is accompanied by secretion of both triglyceride lipase and phospholipase activities, 8 and can provide an alternative pathway for free FA uptake in adipose tissue when the action of LPL is absent.9 EL expression is detected in a variety of tissues, including heart, and EL expression in the heart was increased in animal models of septic shock and hypertension, 10,11 whereas the physiological role of EL in the heart remains unclear. Given its cardiac expression See Editorial Commentary, pp 955-957Abstract-Lipoprotein lipase has been considered as the only enzyme capable of generating lipid-derived fatty acids for cardiac energy. Endothelial lipase is another member of the triglyceride lipase family and hydrolyzes highdensity lipoproteins. Although endothelial lipase is expressed in the heart, its function remains unclear. We assessed the role of endothelial lipase in the genesis of heart failure. Pressure overload-induced cardiac hypertrophy was generated in endothelial lipase −/− and wild-type mice by ascending aortic banding. Endothelial lipase expression in cardiac tissues was markedly elevated in the early phase of cardiac hypertrophy in wild-type mice, whereas lipoprotein lipase expression was significantly reduced. Endothelial lipase −/− mice showed more severe systolic dysfunction with left-ventricular dilatation compared with wild-type mice in response to pressure overload. The expression of mitochondrial fatty acid oxidation-related genes, such as carnitine pa...

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Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.

Cited by 105 publications

References 37 publications

Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and Produce Lipoproteins Enriched in Ceramides and Sphingomyelin

Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and Produce Lipoproteins Enriched in Ceramides and Sphingomyelin

TNF‐α, a potent lipid metabolism regulator

Endothelial Lipase Modulates Pressure Overload–Induced Heart Failure Through Alternative Pathway for Fatty Acid Uptake

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