Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters.

Harðardóttir, Ingibjörg; Moser, Arthur H.; Fuller, John; Fielding, Christopher J.; Feingold, Kenneth R.; Grünfeld, Carl

doi:10.1172/jci118707

Cited by 78 publications

(53 citation statements)

References 49 publications

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“…Notable among the dimorphically induced genes was a TNF␣-induced protein, suggesting a possible differential effect of TNF␣ on target genes. Hepatic TNF␣ is induced by the bile acid-enriched diet, and both CETP and Cyp7a are repressed by TNF␣ (32)(33)(34). DISCUSSION We have shown that the orphan nuclear receptor LRH-1 binds and transactivates the human CETP promoter.…”

Section: Regulation Of Cetp Gene By Bile Salt In Cetp Transgenicmentioning

confidence: 82%

“…Thus, the TNF␣-induced protein 2 was increased in males and decreased in females, suggesting that there could be a dimorphic effect of TNF␣ signaling in male versus female mice. Hepatic TNF␣ expression is induced by the cholic acid diet (it is probably made in Kupffer cells) (33), and TNF␣ has been shown to repress both CETP (34) and Cyp7a (32). If the effect of TNF␣ is larger in male mice, this could explain why CETP is repressed in this sex.…”

Section: Regulation Of Cetp Gene By Bile Salt In Cetp Transgenicmentioning

confidence: 99%

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The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor

Luo

Liang

Tall

2001

Journal of Biological Chemistry

137

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The human cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoproteins to triglyceride-rich lipoproteins, indirectly facilitating cholesteryl esters uptake by the liver. Hepatic CETP gene expression is increased in response to dietary hypercholesterolemia, an effect that is mediated by the activity of liver X receptor/retinoid X receptor (LXR/ RXR) on a direct repeat 4 element in the CETP promoter. In this study we show that the orphan nuclear receptor LRH-1 also transactivates the CETP promoter by binding to a proximal promoter element distinct from the DR4 site. LRH-1 potentiates the sterol-dependent regulation of the wild type CETP promoter by LXR/RXR. Small heterodimer partner, a repressor of LRH-1, abolishes the potentiation effect of LRH-1 but not its basal transactivation of the CETP promoter. Since this mode of regulation of CETP is very similar to that recently reported for the bile salt-mediated repression of Cyp7a (encoding the rate-limiting enzyme for conversion of cholesterol into bile acid in the liver), we examined the effects of bile salt feeding on CETP mRNA expression in human CETP transgenic mice. Hepatic CETP mRNA expression was repressed by a diet containing 1% cholic acid in male mice but was induced by the same diet in female mice. Microarray analysis of hepatic mRNA showed that about 1.5% of genes were repressed, and 2.5% were induced by the bile acid diet. However, the sexually dimorphic regulatory pattern of the CETP gene was an unusual response. Our data provide further evidence for the regulation of CETP and Cyp7a genes by similar molecular mechanisms, consistent with coordinate transcriptional regulation of sequential steps of reverse cholesterol transport. However, differential effects of the bile salt diet indicate additional complexity in the response of these two genes.

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Section: Regulation Of Cetp Gene By Bile Salt In Cetp Transgenicmentioning

confidence: 82%

Section: Regulation Of Cetp Gene By Bile Salt In Cetp Transgenicmentioning

confidence: 99%

The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor

Luo

Liang

Tall

2001

Journal of Biological Chemistry

137

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“…Furthermore, TNF-a reduced the levels of mRNA for CETP in muscle, heart, intestine, stomach, and kidney, but not in adipose tissue while IL-1 was administered together they were much more effective than the individual cytokines and decreased CETP mRNA expression in all the tissues. 80 Injection of TNF to cynomolgus monkeys decreased plasma LCAT activity, plasma cholesterol level, and decreased content of cholesterol ester in LDL and HDL particles. 81 In HepG2 cells, rH-TNF-a dose dependently decreased the concentrations of apolipoprotein (apo) A-I, apoB, and LCAT activity in the medium after 24 h of incubation.…”

Section: Effects Of Tnf-a On Cholesterol Metabolismmentioning

confidence: 98%

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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“…For example, a decrease in PPAR␣ may contribute to the reduced expression of acyl-CoA synthetase (29,34) and carnitine palmitoyltransferase I (45) during the APR. Similarly, a decrease in LXR, LRH, and SHP may contribute to the decrease in cholesteryl ester transfer protein (46). Because many of the proteins regulated by nuclear hormone receptors are involved in the metabolism of triglycer- 5 Hep3B cells were plated in 100-mm Petri dishes in culture media containing 10% serum.…”

Section: Fig 2 Effect Of Lps Treatment On Binding Of Hepatic Nuclearmentioning

confidence: 99%

Repression of Farnesoid X Receptor during the Acute Phase Response

Kim

Shigenaga

Moser

et al. 2003

Journal of Biological Chemistry

140

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The acute phase response is associated with changes in the hepatic expression of genes involved in lipid metabolism. Nuclear hormone receptors that heterodimerize with retinoid X receptor (RXR), such as thyroid receptors, peroxisome proliferator-activated receptors, and liver X receptors, modulate lipid metabolism. We recently demonstrated that these nuclear hormone receptors are repressed during the acute phase response induced by lipopolysaccharide (LPS), consistent with the known decreases in genes that they regulate. In the present study, we show that LPS significantly decreases farnesoid X receptor (FXR) mRNA in mouse liver as early as 8 h after LPS administration, and this decrease was dose-dependent with the half-maximal effect observed at 0.5 g/100 g of body weight. Gel-shift experiments demonstrated that DNA binding activity to an FXR response element (IR1) is significantly reduced by LPS treatment. Supershift experiments demonstrated that the shifted protein-DNA complex contains FXR and RXR. Furthermore, the expression of FXR target genes, SHP and apoCII, were significantly reduced by LPS (70 and 60%, respectively). Also, LPS decreases hepatic LRH expression in mouse, which may explain the reduced expression of CYP7A1 in the face of SHP repression. In Hep3B human hepatoma cells, both tumor necrosis factor (TNF) and interleukin-1 (IL-1) significantly decreased FXR mRNA, whereas IL-6 did not have any effect. TNF and IL-1 also decreased the DNA binding activity to an IR1 response element and the expression of SHP and apoCII. Importantly, TNF and IL-1 almost completely blocked the expression of luciferase activity linked to a FXR response element promoter construct transfected into Hep3B cells. Together with our earlier studies on the repression of RXRs, peroxisome proliferator-activated receptors, LXRs, thyroid receptors, constitutive androstane receptor, and pregnane X receptor, these results suggest that decreases in nuclear hormone receptors are major contributors to the decreased gene expression that occurs in the negative acute phase response.

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Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters.

Cited by 78 publications

References 49 publications

The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor

The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor

TNF‐α, a potent lipid metabolism regulator

Repression of Farnesoid X Receptor during the Acute Phase Response

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