Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.

Feingold, Kenneth R.; Soued, Mounzer; Adi, Saleh; Staprãns, Ilona; Neese, Richard A.; Shigenaga, Judy K.; Doerrler, William T.; Moser, Arthur H.; Dinarello, C A; Grünfeld, Carl

doi:10.1161/01.atv.11.3.495

Cited by 88 publications

(63 citation statements)

References 47 publications

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“…We previously showed that these cytokines stimulate hepatic fatty acid and cholesterol synthesis and increase VLDL production and secretion. [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.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…A close interaction has been described between the innate immune system and lipoprotein metabolism in general and in triglyceride (TG) metabolism in particular ( 6 ). This interaction has largely been derived from studies that evaluated the effects of lipopolysaccharide (LPS), a major component of the cell wall of gram-negative bacteria, and individual cytokines on lipoprotein metabolism (7)(8)(9).…”

Section: H]oleate [Triolein (To)] and [mentioning

confidence: 99%

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Diepen

Stienstra

Vroegrijk

et al. 2013

Journal of Lipid Research

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Obesity is accompanied by low-grade chronic systemic infl ammation characterized by increased circulating levels of proinfl ammatory cytokines, including interleukin (IL)-1 ␤ , tumor necrosis factor (TNF)-␣ , and IL-6 ( 1 ). Activation of infl ammatory pathways induces metabolic disturbances, leading to insulin resistance, dyslipidemia, and cardiovascular diseases. Caspase-1 is a cysteine protease that is known for its crucial role in the activation of the proinfl ammatory cytokines IL-18 and IL-1 ␤ . Additionally, caspase-1 has been shown to cleave other substrates, including proteins involved in energy metabolism ( 2-4 ). Caspase-1 activation is controlled by the infl ammasome, a multiprotein Abstract Caspase-1 is known to activate the proinfl ammatory cytokines IL-1 ␤ and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 defi ciency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-defi cient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-defi cient and wild-type mice. Caspase-1 defi ciency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [ Lipid composition of fecesMice were individually housed for 4 days to determine food intake and collect feces quantitatively. Feces were weighed, freeze-dried, and ground, and fecal fatty acids (FA) were derivatized by methyl esterifi cation. Therefore, 2 ml methanol/hexane (4:1 v/v) containing 80 µg pentadecanoic acid (C15:0) as an internal standard (Fluka) was added to 15 mg of feces. Then, 200 µL acetyl chloride (Merck) was added, and samples were incubated at 95°C. After cooling to 4°C, 5 ml 6% K 2 CO 3 (Sigma) was added, and samples were centrifuged (10 min; 4,000 rpm, 4°C). The upper hexane layer was isolated and used for GC analysis of FA methyl esters (FAME). FAME were separated on a 50 m × 0.25 mm capillary GC column (CP Sil 88; Agilent technologies) in a 3800 GC gas chromatograph (Varian) equipped with a fl ame ionization detector. The injector and fl ame ionization detector were kept at 270°C. The column temperature was programmed from 170°C to 210°C. FAME were introduced by split injection (split ratio 20:1). Quantifi cation was based on the area ratio of the individual FA to the internal standard.To extract total cholesterol from feces, dried feces (10 mg) were incubated in 1 ml alkaline methanol (CH 3 OH: 1 M NaOH = 3:1 [v/v]) for 2 h at 80°C in screw-capped tubes using 5 ␣ -cholestane as internal standard. Tubes were cooled to room temperature, and the cholesterol was extracted twice with 2 ml petroleum ether. The combined petroleum ether layers were evaporated to dryness, and the ...

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“…Among these, changes in lipid metabolism have received much attention due to the link between infection/inflammatory diseases and atherosclerosis (2)(3)(4)(5)(6). The characteristic changes in lipid metabolism during the APR include hypertriglyceridemia (7), decreases in serum high density lipoprotein cholesterol levels (8,9), increased hepatic cholesterol synthesis, inhibition of bile acid synthesis (10), increased hepatic fatty acid synthesis, and decreased hepatic fatty acid oxidation and ketogenesis (11,12). These changes are mediated by alterations in gene expression caused by proinflammatory cytokines including TNF␣, IL-1␤, and IL-6 (10).…”

mentioning

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.

show abstract

Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.

Cited by 88 publications

References 47 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

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Repression of Farnesoid X Receptor during the Acute Phase Response

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