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Alterations in lipid metabolism induced by recombinant bovine tumor necrosis factor-alpha administration to dairy heifers^1,2

S. Kushibiki^*,3, K. Hodate, H. Shingu^*, T. Hayashi, E. Touno^*, M. Shinoda^* and Y. Yokomizo^#

^* Department of Animal Production, National Agricultural Research Center for Tohoku Region, Iwate, 020-0198, Japan; and Kitasato University, Aomori, 034-8628, Japan; and National Agricultural Research Center, Ibaraki, 305-8666, Japan; and and ^# National Institute of Animal Health, Ibaraki, 305-0856, Japan

³ Correspondence:
phone: +81-19-643-3546; fax: +81-19-643-3547; E-mail:
mendoza{at}affrc.go.jp.

	Abstract

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Endotoxin induces marked changes in lipid metabolism via its effects on cytokines. To evaluate the role of tumor necrosis factor-alpha (TNF) in mediating changes of lipid metabolism in ruminants, we performed a crossover saline-controlled study in Holstein heifers (n = 8; 394.0 kg average BW), investigating the metabolic effects of a single intravenous administration of recombinant bovine TNF (rbTNF, 5.0 µg/kg). Blood samples were taken from a jugular vein at 0 (1100, just before injection), 0.5, 6, 12, and 24 h after each treatment. Dry matter intake in the heifers was not affected by single administration of the rbTNF. The rbTNF produced early as well as later hypertriglyceridemia (P < 0.05) in dairy heifers. The rbTNF also induced an early and sustained rise (P < 0.05) in the plasma NEFA concentration. Plasma retinol concentration was decreased (P < 0.05) at 24 h after rbTNF injection, whereas the -tocopherol concentration was not significantly affected by rbTNF treatment. At 0.5 and 24 h, there was an increase (P < 0.05) in the plasma concentration of the very-low-density lipoprotein (VLDL) fraction in rbTNF-treated heifers. Between 6 and 24 h after rbTNF treatment, concentration of the low-density lipoprotein fraction declined (P < 0.05) but the high-density lipoprotein fraction was not altered in the rbTNF-treated heifers. These results indicate that TNF produces a hypertriglyceridemic response associated with an increase of the VLDL fraction and a disturbance of retinol metabolism in dairy heifers.

Key Words: Dairy Cattle • Lipoproteins • Retinol • Tumor Necrosis Factor • Vitamin E Acetate

	Introduction

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The activation of the immune system in response to infection is known to be modulated by cytokines (Dinarello and Mier, 1986). It is now obvious that tumor necrosis factor-alpha (TNF) plays a key role in the initiation and regulation of immune and inflammatory responses (Spurlock, 1997) and has the ability to mediate the induction of hypertriglyceridemia that occurs in association with infection (Grunfeld and Palladino, 1990). The administration of TNF to rats induced a rapid increase in the plasma triglyceride (TG) concentration (Feingold and Grunfeld, 1987). This increase in plasma TG level was due to an increase in very-low-density lipoprotein (VLDL) (Grunfeld and Palladino, 1990). In ruminants, we previously demonstrated that the administration of recombinant bovine TNF (rbTNF) to heifers results in an increase in the plasma TG level at 0.5 h after the treatment (Kushibiki et al., 2000). However, there is no published information on the characteristics of the lipoproteins that are responsible for the disturbance of TG metabolism seen after TNF treatment in ruminants. Retinoids and -tocopherol are important in host defense and immunologic reactivity (Grimble, 1990; Jialal et al., 2001). Retinol is particulary important in maintaining cell-mediated immunity (Grimble, 1990). In humans, it has been implied that retinol present in plasma is a modulator of B lymphocytes function (Blomhoff et al., 1992). Recent data suggest that retinol enhances both Kupffer cell and peripheral blood monocyte function in rats (Hoglen et al., 1997). However, it is not clear whether TNF affects the relationship between immune status and fat-soluble vitamin metabolism in ruminants.

The purpose of the present study was to clarify the effects of intravenous (i.v.) administration of rbTNF on lipoprotein metabolism in dairy heifers. We also determined whether the administration of rbTNF influenced the plasma concentrations of retinol and -tocopherol.

	Materials and Methods

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Animals

Experiments were conducted on eight nonpregnant Holstein heifers (mean ± SE, 394.0 ± 11.8 kg BW, 18 ± 1.2 mo old). The heifers were cared for according to the Guide for the Care and Use of Agricultural Animals in Agricultural Research of the National Agricultural Research Center for Tohoku Region (TNAES, 1998) based on the Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching (Consortium, 1988). The heifers were housed in individual tie stalls with free access to water and a trace mineral block and were allowed to exercise between 1300 to 1600 except on the experiment days. They were fed a diet according to the Japanese feed standard (Agriculture, Forestry, and Fishery Research Council Secretariat, 1999) that was designed to meet the requirements for energy of maintenance and growth (0.5 kg BW/d). The diet consisted of 31.3% orchardgrass hay, 3.7% alfalfa hay cube, 15.0% corn silage, and 50.0% mixed concentrate (dry matter basis). Feed was provided twice daily at 0830 to 1030 and 1700 to 2000. Dry matter intake (DMI) was recorded for each heifer from 2 d prior to challenge (0 d) until 2 d after challenge. During the experimental period, average ambient temperature was 13 to 21°C, and the cow house was illuminated between 0630 and 2300.

Experiments

Highly purified recombinant bovine TNF (17 kDa) was kindly provided by Higeta Shoyu Co., Ltd., Choshi, Japan (Udaka and Yamagata, 1993). This rbTNF was used for the following experiments. The experimental periods were 24 h in duration, starting at 1100. Each heifer was studied two times with an interval of 3 wk. In the first period, four heifers received an i.v. injection of rbTNF (5.0 µg/kg BW) and the others received an i.v. injection of physiological saline (40 mL). During the subsequent period, heifers received alternate treatments. The rbTNF was dissolved in 40 mL of physiological saline solution. A disposable catheter (19G needle, 70 mm, Top Co. Ltd., Tokyo, Japan) was placed in the right jugular vein prior to the experimental starting. This catheter was used for the administration of agent and removed immediately following the end of treatment.

Blood Samples. All blood samples (12 mL) were collected by venipuncture from the left jugular vein into tubes containing Na₂-EDTA (final concentration, 1 mmol/L) at 0 (1100, just before injection), 0.5, 6, 12, and 24 h after each treatment. The heifers were restrained just during period of blood sampling (30 to 40 s). Plasma was then separated by centrifugation at 3,500 x g for 15 min at 4°C. A portion of each plasma sample (2 mL) was stored at -20°C for later determinations of the metabolites and vitamins indicated below. The remainder of the plasma was supplemented with NaN₃ (final concentration of 0.01%, wt/vol) and maintained at 4°C until lipoprotein fractionation, usually within 24 h.

Lipoprotein Isolation. The procedures used for separating lipoprotein fractions were essentially those of Hatch and Lees (1968). All ultracentrifugations were performed with a Beckman type MLA-130 rotor (Beckman Instruments, Fullerton, CA) in a Beckman Optima Max ultracentrifuge. Three main lipoprotein classes were prepared using the following density intervals recommended for ruminants (Jenkins et al., 1988): VLDL, < 1.006 g/mL; low-density lipoprotein (LDL), 1.006 to 1.063 g/mL; high-density lipoprotein (HDL), 1.063 to 1.21 g/mL. The VLDL fraction was first removed from the plasma by ultracentrifugal flotation for 60 min at 1,000,000 x g at 15°C. The LDL and HDL fractions were then separated from VLDL-free plasma by ultracentrifugation for 150 min at 1,000,000 x g and 15°C, in a discontinuous density gradient, as described by Hatch and Lees (1968).

Chemical Analysis. The concentrations of TG, NEFA, total-cholesterol (TC), free cholesterol (FC), and phospholipid (PL) in all plasma samples or lipoprotein fractions were determined enzymatically by a Hitachi 7070 automatic analyzer (Hitachi, Co., Ltd., Tokyo, Japan). The cholesterol ester (CE) content was calculated using the relationship of CE = (TC - FC) x 1.68 (Bauchart et al., 1989). Intraassay and interassay coefficients of variation for measurement of TG, NEFA, TC, FC, and PL were less than 1% and 2%, respectively.

The 0-, 6-, 12-, and 24-h samples were analyzed for retinol and -tocopherol. The plasma retinol concentration was determined by reverse-phase HPLC using a modification of the method (Shimadzu HPLC Application Report, No. 9) of McCormik et al. (1978). The HPLC column consisted of a 150-x 6-mm, CLC-ODS column (Shimadzu Co., Ltd., Tokyo, Japan) and the mobile phase was a 90:10 (vol/vol) mixture of methanol/double-distilled water supplemented with sodium acetate (2 mmol/L). The plasma -tocopherol concentration was measured by reverse-phase HPLC using a modification of the method (Shimadzu HPLC Application Report, No. 9) of McMurray et al (1980). The HPLC column was the same one used for retinol, and the mobile phase consisted of methanol. The extractions of retinol and -tocopherol from plasma were performed as described by Abe and Katsui (1975). The intraassay coefficients of variation of retinol and -tocopherol were 2% and 2%, respectively.

Statistical Analysis

The various characteristics (DMI, plasma lipid and lipoprotein concentrations, and compositions of the lipoprotein classes) studied using the different treatments were analyzed using the repeated measures analysis of variance format outlined for the GLM procedure of SAS (SAS Inst. Inc., Cary, NC). The sources of variation in the model included the heifers, treatments, sampling time, and the interaction of treatment x sampling time. Responses to rbTNF administration were compared with responses to control at each time point using this model. Differences between responses to treatments were considered significant at P < 0.05.

	Results

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DMI, Blood Metabolites, and Vitamins

DMI between -2 and 2 d did not differ (P > 0.05) between treatment groups, although a slight decrease (1.8%) in DMI on the experimental d 0 in heifers treated with rbTNF compared to control heifers was observed (Table 1).

View larger version (17K): [in this window] [in a new window]   Figure 1. Time course (24 h) of the effects of a single i.v. administration of rbTNF (5.0 µg/kg; ) or saline () on the plasma concentrations of triglyceride (upper panel) and NEFA (lower panel). Data are presented as means ± SE for eight heifers. Asterisks mark significant differences between rbTNF and saline heifers (*P < 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 2. Time course (24 h) of the effects of a single i.v. administration of rbTNF (5.0 µg/kg; ) or saline () on the plasma concentrations of retinol (upper panel) and -tocopherol (lower panel). Data are presented as means ± SE for eight heifers. Asterisks mark significant differences between rbTNF and saline heifers (*P < 0.05).

Table 2 shows the effects of a single injection of rbTNF or saline to heifers on the total lipid concentrations and the proportions of subfraction in the VLDL class. In the rbTNF-treated heifers, the change in the total lipid concentration in the VLDL class was similar to the change in plasma TG. The total lipid concentration and the proportion of TG in the VLDL class were higher (P < 0.05) in the rbTNF-treated heifers than in the saline-treated heifers at 0.5 and 24 h after the administration. At 6 h after the rbTNF treatment, however, the total lipid concentration and TG ratio in the VLDL fraction were lower (P < 0.05) than those for the saline treatment. In contrast, the percentages of CE and FC in the rbTNF group were higher (P < 0.05) than those in the control group at 6 h after injection. The PL ratio in the VLDL fraction was lower (P < 0.05) in the rbTNF-treated heifers than in the saline-treated heifers at 0.5, 12, and 24 h after the injection.

	Discussion

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Infectious diseases frequently result in systemic metabolic changes such as hypertriglyceridemia (Gallin et al., 1969). A recent study suggested that these effects of infection may be mediated by TNF (Sethi and Hotamisligil, 1999). The administration of TNF to humans also increases serum TG level (Van Der Poll et al., 1991). A previous study in ruminants also showed that the concentration of plasma TG was elevated in heifers at 0.5 h after an i.v. injection of rbTNF (Kushibiki et al., 2000). Two possible mechanisms whereby TNF could increase plasma TG have been suggested (Grunfeld and Palladino, 1990). First, by inducing an increase in de novo hepatic lipogenesis, TNF could produce increased hepatic secretion of VLDL and TG-rich lipoproteins. Alternatively, by decreasing peripheral lipoprotein lipase (LPL) activity, TNF could induce a decrease in the clearance of TG-rich particles such as VLDL. Indeed, treatment of rats with TNF produced a rapid increase in the level of plasma VLDL of normal magnitude (Krauss et al., 1990). The VLDL increase coincides with the timing of the hepatic fatty acid and glyceride synthesis that has been reported previously (Feingold and Grunfeld, 1987). As seen with infection, TNF rapidly stimulates hepatic lipogenesis (Feingold and Grunfeld, 1987). On the other hand, LPL activity is not decreased acutely following TNF treatment (Grunfeld et al., 1989). In the present study, it was demonstrated that rbTNF rapidly and sustainedly increases the circulating levels of NEFA in dairy heifers. Therefore, in this study, it is possible that rbTNF induced a rapid increase in plasma TG concentration by increasing the production and secretion of VLDL in the liver rather than by reduction of LPL in adipose tissues. However, in rats, single injection of recombinant human TNF induced an initial increasd in plasma concentrations of TG and VLDL between 1 and 2 h after treatment (Feingold and Grunfeld, 1987; Krauss et al., 1990). The mechanism by which rbTNF induced an initial hypertriglyceridemia in the present study needs to be validated. In contrast, it seems likely that rbTNF increases the level of plasma TG in the late phase by effects on the liver plus inhibition of LPL in adipose tissues.

The rbTNF injection elicited a pronounced hypotriglyceridemic response at 6 h after the treatment in the present study. Timing of this change was remarkably similar to that for the change in plasma TG seen in a previous study (Kushibiki et al., 2000). It has been reported that continuous intraperitoneal infusion of TNF (4.0 and 8.0 (g/d) induced a dose-dependent decrease in the plasma level of TG in rats (Sweep et al., 1992), and the same study speculated that TNF treatment inhibits the rate of gastric empty and gastrointestinal motility and results in a markedly decreased absorption of orally administered lipids (Sweep et al., 1992). In the present study, the TG subfractions of both the VLDL and LDL fractions at 6 h after the rbTNF injection decreased, compared with those after the saline injection. In contrast, the rbTNF treatment produced increases of the CE and FC subfractions in VLDL and LDL, compared with the levels of saline treatment at 6 h after the administration. It is possible that rbTNF decreased or inhibited the hepatic TG synthesis at that time point and induced a decrease in hepatic VLDL and LDL secretion.

The present study also demonstrated that a decrease in the LDL level occurs between 6 and 24 h after rbTNF administration. A recent report indicated that inflammatory cytokines may alter the LDL metabolism in cultured cells, including monocytes (Klein et al., 2001). When human monocytes or murine endothelial cells are incubated with TNF, the oxidation of LDL is increased (Maziere et al., 1994). In addition, it has been shown that TNF rapidly (within several hours) up-regulates the expression of the LDL receptors on human hepatocytes (Liao and Floren, 1994). Therefore, it is possible that rbTNF-induced LDL catabolism and up-regulation of the LDL receptor activity mediate a decrease of plasma LDL concentration, although the relationship between TNF and LDL metabolism is presently poorly understood in ruminants.

There were no major differences in HDL mass or composition between the control and the rbTNF-treated heifers, although at 24 h there was a slight increase in the proportion of TG in HDL in the rbTNF group. These results are in agreement with the findings of the in vivo study in rats that showed that there is little or no change in HDL mass or composition after recombinant human TNF treatment (Krauss et al., 1990).

Several studies have shown that retinoids are important for the maintenance of immune status (Gross and Newberne, 1980; Grimble, 1990). In humans, the acute inflammatory response to infection is associated with low concentrations of plasma retinol and its specific transport protein, retinol-binding protein (RBP) (Arroyave and Calcano, 1979). Indeed, lipopolysaccharide treatment of rats induced a decrease in plasma retinol concentration and a reduction of the hepatic synthesis of RBP and secretion of the retinol-RBP complex (Rosales et al., 1996). The present study also demonstrated that rbTNF administration decreased the level of plasma retinol in heifers. This in vivo observation suggests that rbTNF may influence the immune state in ruminants.

Alpha-tocopherol is the most active component of the vitamin E family and has anti-inflammatory effects on immunocytes such as monocytes (Jialal et al., 2001). A Finnish field study found that concentration of -tocopherol in plasma was lower in mastitic cows than in a healthy herd (Atroshi et al., 1986). However, acute inflammation caused by endotoxin or Esherichia coli had no effect on concentration of plasma -tocopherol in cows (Hogan et al., 1996; Barrett et al., 1997). In the present study, the concentration of plasma -tocopherol in the heifers was not affected by the single administration of rbTNF. Further studies are needed to clarify whether TNF affects the plasma -tocopherol concentration.

In summary, the present study demonstrated that in vivo administration of rbTNF can lead to an increase in plasma TG concentration, suggesting that there is a strong linkage between the hypertriglyceridemic response and lipoprotein metabolism. In addition, it was demonstrated that a single injection of rbTNF to heifers induces a decrease in plasma retinol concentration. This is the first study demonstrating that rbTNF alters lipid metabolism in ruminants. Thus, it is likely that TNF is an in vivo mediator of such metabolic changes in the acute phase of bacterial infection.

	Implications

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These results are consistent with the hypothesis that the production of TNF plays an important role in regulating lipid metabolism during immune challenge. The mechanisms of the in vivo lipolytic effects of TNF remain to be established. However, these results suggest that the liver is one of major sites of action involved in the metabolic effects of rbTNF. It is possible that increased transport of lipids and hyperlipidemia induced by rbTNF may be a part of the host’s self-protective response to infection.

	Footnotes

 
¹ This study was supported by a Grant-in-Aid of Recombinant Cytokine’s Project provided by the Ministry of Agriculture, Forestry and Fisheries, Japan (RCP 2001–4330).

² The authors thank S. Osaki and F. Kushibiki for help with the experiments.

Received for publication November 22, 2001. Accepted for publication April 5, 2002.

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