1alpha,25-Dihydroxyvitamin D and fish oil synergistically inhibit G1/S-phase transition in prostate cancer cells.

Laboratory and epidemiological studies have indicated that 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and dietary omega3-polyunsaturated fatty acids (PUFAs) are capable of inhibiting prostate cancer at the initiation and progression stages. The objective of this study is to investigate the influence of 1alpha,25(OH)(2)D(3) and PUFAs in the form of fish oil applied alone or in combination on cell cycle kinetics in the exponentially growing androgen-dependent and -independent prostate cancer cells. Our data indicate that the high passage androgen-independent cell line, LNCaP-c115 had a much greater inhibitory response at the level of the G(1)/S-phase transition in response to fish oil treatment than androgen-dependent low passage LNCaP-c38 cells. When LNCaP-c38 and LNCaP-c115 cells were treated with fish oil (50mug/ml), 1alpha,25(OH)(2)D(3) (10(-8)M) or fish oil (50mug/ml)+1alpha,25(OH)(2)D(3) (10(-8)M), a synergistic growth inhibitory effect was observed with 1alpha,25(OH)(2)D(3)+fish oil group in LNCaP-c115 cell line at the levels of the G(1)/S-phase transition and cell division. This interaction appears to be specific for androgen-independent prostate cancer cell lines. Based on these results, we hypothesize that dietary components, such as omega3PUFAs and Vitamin D, have the potential to delay the progression of prostate cancer cells to an aggressive and un-treatable state.

Docosahexaenoic acid, a major constituent of fish oil diets, prevents activation of cyclin-dependent kinases and S-phase entry by serum stimulation in HT-29 cells.

Cellular proliferation is regulated by cell cycle progression which, in turn, is controlled by sequential activation of various cyclin-dependent kinases (CDKs). To explore the mechanism(s) by which long chain polyunsaturated fatty acids (PUFAs) influence the growth of tumor cells, we compared the effects of different n-3 and n-6 fatty acids on the activity of CDKs. Docosahexaenoic acid (DHA), a major component of fish oil diets, is able to reduce serum-stimulated cyclin D1-, E-, and A- associated kinases activity in synchronized-HT-29 cells. The inhibitory effect of DHA on cyclin A-associated kinase activity is time-dependent, and is probably modulated by down-regulation of cyclin A protein expression. In addition, DHA inhibits the phosphorylation of pRb and DNA-binding activity of E2F-1 in response to serum stimulation, and prevents the serum-stimulated entry of S-phase in HT-29 cells. These results indicate that DHA may exert its negative effect on the growth of tumor cells by inhibiting the activation and expression of G1-associated cell cycle regulatory proteins. Since the synthetic antioxidant BHT is able to reverse the inhibition of serum-stimulated activation of cyclin A/CDK by DHA in a dose-dependent manner, endogenous oxidative stress produced by lipid peroxidation in HT-29 cells may be involved in the control of cell cycle progression.

Docosahexaenoic acid is a potent inducer of apoptosis in HT-29 colon cancer cells.

Some studies have shown that dietary intake of polyunsaturated fatty acids of the n-3 series may have inhibitory effect on the growth of tumor cells both in vivo and in vitro. However, the cellular and molecular mechanisms by which n-3 fatty acids reduce the growth of tumor cells remain poorly understood. In the present studies, we compared the potency of a variety of n-3 and n-6 fatty acids in modulating the apoptotic cell death in HT-29 colon cancer cells. Of all fatty acids examined, we found that docosahexaenoic acid (22:6n-3; DHA) is a potent inducer of apoptosis in a time- and dose-dependent manner. Indomethacin, a cyclooxygenase inhibitor, is ineffective in blocking the apoptosis induced by DHA, suggesting that DHA-induced apoptosis in HT-29 cells is not mediated through the cyclooxygenase pathway. In contrast, the DHA-induced apoptosis is partially reversed by a synthetic antioxidant, butylated hydroxytoluene, indicating that lipid peroxidation may be involved in apoptotic signaling pathway induced by DHA. DHA treatment decreased bcl-2 levels in association with apoptosis, whereas bax levels remained unchanged. These results suggest that decreased expression of bcl-2 by DHA might increase the sensitivity of cells to lipid peroxidation and to programmed cell death.

Fish oil feeding improves muscle glucose uptake in tumor necrosis factor-treated rats.

This study was conducted to characterize the effects of fish oil and sunflower oil on hepatic glucose production and peripheral glucose utilization during infusion of saline or tumor necrosis factor (TNF), using the euglycemic-hyperinsulinemic clamp technique combined with a primed-constant tracer infusion of high-performance liquid chromatography-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates. Insulin 10 mU/kg.min was infused to reach a plasma insulin level of 200 microU/mL. 14C-1-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. The results showed that during a hyperinsulinemic-euglycemic clamp, infusion of TNF 20 micrograms/kg for 3 hours resulted in a significant reduction of glucose infusion and a significant increase of hepatic glucose production in both dietary groups as compared with saline infusion, indicating a state of insulin resistance induced by TNF. The results also showed that TNF infusion significantly decreased the rate of 14C-DG uptake in muscle in the sunflower oil group but not in the fish oil group, suggesting that fish oil is able to restore to normal the glucose utilization impaired by TNF. These observations suggest that in hyperinsulinemic and euglycemic conditions, prefeeding with fish oil significantly improves glucose uptake in muscle tissue, but does not alter the increase in hepatic glucose production during TNF infusion.

Differential effects of interleukin-1 receptor antagonist in cytokine- and endotoxin-treated rats.

Previous studies have demonstrated that the administration of the cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF)(20 micrograms/kg) to rats in a fasting state can produce many and perhaps most of the metabolic alterations found in patients with sepsis and injury. The purposes of the present study were 1) to define the metabolic effects of IL-1 and TNF during a fed state provided by continuous intravenous feeding for 20 h and 2) to characterize the unique effects of IL-1 among the overall response to cytokines by using IL-1 receptor antagonist (IL-1RA; 5 mg/kg). The effects were also explored during the endotoxemic condition induced by infusion of 200 micrograms/kg of endotoxin into rats. The results showed that during feeding IL-1 is responsible for the increase in glucose flux and plasma insulin, the development of insulin resistance, and plasma zinc depression during condition mimicking sepsis and injury, similar to effects observed in the fasting state. The changes in energy expenditure have a more complex mechanism. The results also suggested that certain host responses to cytokines or endotoxin, particularly related to protein metabolism, differed between the fed and fasting states. These data may have a special clinical relevance for the insulin-resistant state that develops during severe infection, since using IL-1RA in conjunction with nutritional therapy may offer additional advantages in the treatment of these severe metabolic disorders.

IGF-I alters energy expenditure and protein metabolism during parenteral feeding in rats.

In this study, 20 micrograms.kg.-1.h-1 of recombinant human insulin-like growth factor I (IGF-I) was infused into normal healthy rats to examine the effects of IGF-I on glucose, protein, and energy metabolism in either overnight-fasting or parenteral-feeding states. The fed state was maintained by continuous intravenous feeding of a complete diet containing 838 kJ.kg-1.d-1, 2 g N.kg-1.d-1, and no fat. At each nutritional state, one-half of the animals received IGF-I infusion while the other half received saline as control. [14C-1]leucine and [3H-6]glucose were used to determine the effects of IGF-I on protein and glucose kinetics during fed and fasting states. The results showed that 1) infusion of IGF-I at this amount did not alter plasma glucose appearance and only marginally decreased plasma glucose concentrations in both nutritional states; 2) during fasting, IGF-I did not show anabolic effects on protein metabolism either at the whole-body level or in individual tissues. However, during feeding, IGF-I significantly stimulated exogenous nitrogen utilization by the whole body; and 3) IGF-I reduced the thermogenic effect of feeding. The results suggest that parenteral feeding may be an important variable in the response of protein anabolism to IGF-I in vivo.

Insulin-like growth factor-1 is not mitogenic for the Walker-256 carcinosarcoma.

This study was designed to determine whether intravenous infusion of recombinant human insulin-like growth factor 1 (IGF-1) stimulates tumor growth. In order to determine the potential interaction between nutrition and IGF-1 administration the study was conducted in fasting rats and during continuous feeding by total parenteral nutrition. Tumor cell cycle kinetics including labeling index, DNA synthesis time, cell cycle time in Go/G1, and G2/M in the total cell cycle, and potential doubling time were determined by flow cytometry after in vivo pulse labeling the rats bearing the Walker-256 Carcinosarcoma with 5'-bromo-2'-deoxyuridine (BrdUrd). The results show that IGF-1 treatment has no significant effects on the proliferative characteristics of the tumor model regardless of the feeding status of the animal. This study provides preliminary cell-cycle kinetics data on the short-term effect of IGF-1 on tumor growth. Failure to show a significant effect of IGF-1 on the proliferative characteristics of the tumor suggests that IGF-1 may be given to cancer patients in amounts sufficient to promote weight gain without deleterious stimulation of tumor proliferation.

Fish oil and cell proliferation kinetics in a mammary carcinoma tumor model.

In vivo bromodeoxyuridine (BrdUrd) labelling and bivariate BrdUrd/DNA analysis was used to evaluate cell cycle kinetics in a rat tumor model known to be sensitive to dietary fatty acid manipulation. Fish oil supplementation significantly reduced the rate of BrdUrd movement relative to DNA content, indicating prolongation of the DNA replication time. This finding, which accounted for most of the decrease in tumor growth rate in the fish oil-fed group, represents the first description of an alteration in S phase duration by an extrinsic factor. The significance of this finding is discussed in relation to current understanding of cell cycle regulation. Fish oil feeding is associated with slower growth rate in certain tumors (1,2). According to current concepts of cellular proliferation (3), regulation of growth by extrinsic factors is thought to precede the S phase. This statement is based on the notion that, within a given cell type, DNA replication time (S phase duration) is constant (4-6). Extensive evidence also supports an on/off mechanism of cell cycle regulation at the level of entry into the S phase (3). In this report, we present evidence showing, for the first time, that the S phase duration of fat-responsive tumor cells can be altered by dietary manipulation of fatty acids. Furthermore, these differences in S phase duration appear to account for all the in vivo variation in tumor growth resulting from fish oil feeding. Although the mechanism of this phenomenon remains unclear, our observations support increasing evidence for a regulatory step at the level of the nucleus. They are also important for understanding the relationship between dietary fat and tumor growth.

DNA replication time accounts for tumor growth variation induced by dietary fat in a breast carcinoma model.

Female Fischer rats were pair-fed on diets containing either safflower oil (SO) or fish oil (FO) for 6 weeks. Implanted breast 13762 MAT tumors had a doubling times of 35.4 and 55.5 h in SO and FO rats, respectively (P < 0.001). Proliferation kinetics were measured in vivo by bromedeoxyuridine (BrdUrd) labeling and bivariate DNA/BrdUrd analysis by flow cytometry. After 1 h of pulsing, the labeling index was similar in both groups. However, 6 h later, tumor cells from FO rats had significantly lower relative movement of BrdUrd-labeled cells (0.78 vs. 0.91, P < 0.001). These results reflected a significantly longer S phase duration (15.0 vs. 9.1 h, P < 0.001) in FO rats and accounted for all the difference in tumor growth rates. This mechanism, which has not previously been reported, implies a significant role for fatty acids in DNA replication.

Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake.

This study was performed to characterize and compare the actions of insulin on hepatic glucose production and peripheral glucose utilization during infusions of endotoxin, tumor necrosis factor (TNF), interleukin-1 (IL-1), and a combination of IL-1 and TNF in the rat. The euglycemic hyperinsulinemic clamp technique was combined with a primed-constant tracer infusion of high-performance liquid chromatography (HPLC)-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates; 14C-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. As expected, acute endotoxemia resulted in a significant reduction of glucose infusion during the clamp procedure (insulin concentration, 100 microU/mL), suggesting decreased insulin action. Similarly, infusion of TNF decreased the rate of glucose infusion necessary to maintain euglycemia. However, differences between endotoxin- and cytokine-treated rats were noted in whole-body glucose appearance (or disappearance) rates. Whereas endotoxin infusion predominantly decreased whole-body glucose uptake, suggesting diminished utilization in skeletal muscles, cytokine infusions were associated with a measurable hepatic glucose output despite hyperinsulinemia. In contrast, both cytokine and endotoxin administration decreased the rate of 14C-DG uptake by muscle tissue. These results demonstrate that TNF, IL-1, and endotoxin can induce a state of insulin resistance when infused continuously; the results also emphasize the complexity of regulation of glucose homeostasis during infection and sepsis.

Influence of interleukin-2 infusion on cell cycle kinetics in the Walker-256 carcinosarcoma.

The effect of recombinant human interleukin-2 (IL-2) on tumor cell cycle kinetics was evaluated in rats bearing the Walker-256 carcinosarcoma. Seven days after implantation, tumor-bearing rats were infused intravenously with IL-2 at a dose of 500 mg/kg body weight or 5% dextrose for 6 h. Tumor cell mean DNA synthesis time (TDNA), labeling index, potential doubling time (Tpot), and growth fraction (GF) were determined in vivo by use of bromodeoxyuridine (BrdUrd) pulse labeling and bivariate BrdUrd/DNA analysis using flow cytometry. IL-2 treatment significantly reduced the relative number of S-phase cells by 11.9% and increased the number of cells in the G0/G1 phase by 9.4%. The labeling index was reduced from 41.3 +/- 2.5% to 32.7 +/- 1.2% (P < .01). Estimates of TDNA derived from the change in BrdUrd movement relative to DNA content were not affected by IL-2 treatment. Based on these cytokinetic changes, IL-2 infusion significantly increased tumor Tpot from 15.3 +/- 0.3 h to 21.5 +/- 0.2 h (P < .001) and reduced GF from 1.01 +/- 0.07 to 0.83 +/- 0.01 (P < 0.001). The inhibitory effect of IL-2 infusion on tumor cell growth, which may be either direct or secondarily mediated by other factors, contrasts with other stimulatory effects of this cytokine on lymphoid cell proliferation.

Cell-cycle kinetics of permanent glioma-cells measured by pulse labeling with bromodeoxyuridine.

Cell phase distribution and cycle kinetics of six human glioblastoma cell lines were characterized after labelling with 5-Bromo-2-deoxyuridine (BrdUrd). Cycle time (T(c)), DNA synthesis time (T(s)), and potential doubling time (T(pot)) were compared with the actual doubling time (T(d)) of the growing cell population. Mathematical estimates closely correlated with T(d). Low labelling index (LI) correlated with short T(s) and vice versa. T(s) and LI allowed grouping of the cell lines in two clusters. The mean number of silver stained nucleolar organizer regions (mAgNORs) and percentage of cells with more than five AgNORs (pAgNOR) were counted. AgNORs closely related to LI. Low mAgNORs and pAgNORs correlated with fast T(s) among the clustered cell lines.

Evaluation of antitumor effect of tumor necrosis factor in terms of protein metabolism and cell cycle kinetics.

To determine the significance of protein breakdown in regulating tumor growth and to better understand the antitumor mechanism of tumor necrosis factor in vivo, we measured the effects of a 6-h constant intravenous infusion of human recombinant tumor necrosis factor-alpha (rHuTNF) on tumor protein metabolism and cell cycle kinetics in rats bearing the Walker-256 carcinosarcoma. Protein metabolism was investigated with the use of [14C]leucine infusion; estimates of tumor cell cycle kinetics were obtained in vivo by use of 5-bromo-2'-deoxyuridine (BrdUrd) pulse labeling and bivariate BrdUrd/DNA analysis by flow cytometry. Reduction in tumor growth by rHuTNF was associated with a dose-dependent increase in tumor proteolysis but no change in tumor protein synthesis. At the cellular level, rHuTNF had a significant cytostatic effect on G2/M cells and caused a marked decrease in the fraction of cells capable of BrdUrd uptake. Release of BrdUrd, an indicator of cell death, was noted in only 7.5% of tumor cells labeled at the beginning of rHuTNF infusion. These results suggest that either tumor protein breakdown may influence cell cycle activity by regulating cytoplasmic protein mass or that tumor proteolysis may be a compensatory mechanism for limiting cytoplasmic size when cellular division is interrupted suddenly.

Insulin modulates circulating endothelin-1 levels in humans.

Recent data indicate that insulin stimulates synthesis of the vasoconstrictor peptide endothelin-1 (ET-1) by cultured vascular endothelial cells in vitro. To determine whether insulin modulates ET levels in vivo and whether this effect is important in the pathogenesis of obesity-associated hypertension, we measured circulating immunoreactive ET-1 levels during euglycemic hyperinsulinemic clamps (20 mU/m2.min-1 for 120 minutes) in eight obese women (body mass index, 36 +/- 1 kg/m2) before and after 10 weeks on an 800-kcal/d protein-sparing liquid diet. During the clamp that preceded weight loss, insulin levels were increased from 17 +/- 2 to 51 +/- 3 mU/L and this was associated with an increment in ET-1 level from 28 +/- 3 to 33 +/- 3 pg/mL (P < .05). After weight loss, insulin levels were increased from 10 +/- 2 to 47 +/- 3 mU/L during the clamp, and there was a corresponding increase in ET-1 levels from 24 +/- 3 to 30 +/- 3 pg/mL (P < .025). The reduction in basal ET-1 level (from 28 +/- 3 to 24 +/- 3 pg/mL) with weight loss correlated strongly with the reduction in fasting immunoreactive insulin level (from 17 +/- 2 to 10 +/- 2 mU/L; r = .92, P < .01). The decrease in blood pressure with weight loss (from 130 +/- 6/73 +/- 3 to 118 +/- 4/72 +/- 3 mm Hg) did not correlate with the corresponding reduction in circulating ET-1 levels. These results indicate that insulin modulates ET-1 levels in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of fish oil on glucose metabolism in the interleukin-1 alpha-treated rat.

Fish oil has been demonstrated to ameliorate many of the responses to infection. This study was conducted to determine whether fish oil feeding could modify the alterations of glucose metabolism induced by interleukin-1 alpha (IL-1 alpha) infusion in the rat. Male Sprague-Dawley rats were pair-fed for 5 weeks on two experimental diets in which the source of fat was either fish oil or soybean oil and provided 20% of calories; the diets were isonitrogenous and isocaloric. After 5 weeks of feeding, rats from both diet regimens were further divided into two subgroups to receive a 3-hour infusion of either 0.1% albumin in saline or 0.1% albumin in saline containing IL-1 alpha. A total of 20 micrograms/kg IL-1 alpha was administered, and half the dose of IL-1 alpha was given as a bolus and the remaining portion (10 micrograms/kg) was continuously infused into the jugular vein. During the last 2 hours of IL-1 alpha infusion, a primed constant infusion of D-(6-3H)glucose and D-(U-14C)glucose was combined to determine the effects of IL-1 alpha and diet on glucose kinetics. Plasma levels of glucose and insulin, energy expenditure, and respiratory quotient were also measured. IL-1 alpha significantly increased concentrations of plasma insulin and the percentage of glucose carbon recycling, confirming previous findings. Concentrations of glucose and insulin with IL-1 alpha treatment were significantly higher in soybean oil- fed animals compared with fish oil-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of different lipid sources in total parenteral nutrition on whole body protein kinetics and tumor growth.

This study examined the short-term effects of three total parenteral nutrition solutions, each containing a different lipid source, on host and tumor protein metabolism in a rat cancer model. Each diet contained 220 kcal/kg per day, including 2 g of nitrogen/kg per day and 50% of nonprotein calories as either a structured lipid of medium-chain triglycerides and fish oil, a physical mix of medium-chain triglycerides and fish oil, or Liposyn II, a long-chain triglyceride. A 3-day intravenous feeding infusion began on day 7 after tumor implantation. Tumor growth rate, nitrogen balance, energy expenditure, and plasma albumin, glucose, and free fatty acids were measured, and whole body protein kinetics and fractional synthetic rates in liver, muscle, and tumor tissues were assessed using a constant infusion of 14C-leucine. The results revealed that tumor growth rate was slowed in structured lipid-fed animals (p = .06, one-way analysis of variance) with significant increases in rates of tumor protein synthesis and tumor protein breakdown (p < .001, one-way analysis of variance). Although muscle fractional synthetic rates were significantly decreased in tumor-bearing animals (p < .05, two-way analysis of variance), the rates in structured lipid-fed animals were restored. Nitrogen balance improved significantly in structured lipid-fed animals. The results demonstrate that the source of lipid in total parenteral nutrition solutions can influence tumor and host protein metabolism, and that a structured lipid composed of medium-chain triglycerides and fish oil seems to improve protein metabolism in host tissue without stimulating tumor growth.

Nutrition and tumor promotion: in vivo methods for measurement of cellular proliferation and protein metabolism.

The notion that tumors act as "nitrogen traps" has led to the belief that nutrition support of the cancer-bearing patient can enhance tumor growth. Proponents of this theory consider the provision of energy and essential nutrients as well as the influence of hormones and growth factors as responsible for this effect. On the other hand, nutrition administration in the debilitated cancer patient may improve antitumor host defense mechanisms and reduce tumor growth. This paper reviews methodologic issues related to the study of nutrition and cancer growth with emphasis on in vivo methods for measuring tumor protein turnover and cytokinetics. Using this combined approach, we previously demonstrated that dietary fat may significantly regulate tumor growth during chronic feeding as well as with short-term intravenous nutrition support in experimental models. Although the mechanism of this effect remains unclear, we have reasoned that by altering arachidonic acid metabolism and prostaglandin synthesis, omega-3 fatty acids could change tumor protein breakdown rates and inhibit the proliferation potential of these tumors. Acknowledging alternative hypotheses, we now present cytokinetic evidence that intracellular protein degradation may regulate tumor cell proliferation. Additional studies relating dietary fat, tumor protein metabolism and tumor proliferation potential are currently in progress. We propose that the effect of nutrition administration on tumor growth is complex and involves several regulatory systems. Thus, based on available evidence, an a priori tumor-enhancing effect for nutrition support is clearly not warranted. Intracellular protein breakdown and host defense mechanisms, both of which are energy dependent, are important loci at which nutrition and tumor growth regulation could interact.(ABSTRACT TRUNCATED AT 250 WORDS)

Disparate effects of weight loss on insulin sensitivity and erythrocyte sodium-lithium countertransport activity.

Previous investigations have demonstrated an association between impaired insulin sensitivity and elevated erythrocyte sodium-lithium countertransport (Na(+)-Li+ CT) activity. It has been speculated that insulin resistance and endogenous hyperinsulinemia are causally related to the development of elevated Na(+)-Li+ CT activity. To test this hypothesis, we measured insulin sensitivity (euglycemic insulin clamp technique) and Na(+)-Li+ CT activity in eight obese women before (weight = 102 +/- 5 kg) and after (weight = 88 +/- 5 kg; P < .001) a 10 week weight reduction program. Maximal velocity of Na(+)-Li+ CT activity did not change (0.50 +/- 0.09 v 0.49 +/- 0.10 mmol/L red blood cells/h; P = NS) despite the significant improvement in insulin sensitivity (73 +/- 12 vs 110 +/- 7 mg/m2/min; P < .0025) and reduction in fasting insulin levels (17 +/- 2 v 10 +/- 2 microU/mL; P < .05) that accompanied weight loss. These results suggest that insulin resistance and hyperinsulinemia are not linked pathophysiologically to the development of elevated Na(+)-Li+ CT activity.

Influence of omega-3 fatty acids on splanchnic blood flow and lactate metabolism in an endotoxemic rat model.

Alteration in regional blood flow is important in the pathogenesis of organ failure during endotoxemia and sepsis. In particular, intestinal ischemia is thought to enhance the translocation of bacteria into the systemic circulation. We used radioactive microspheres to measure the influence of two intravenous (IV) dietary fats (vegetable oil containing high levels of omega-6 fatty acids, and fish oil containing high levels of omega-3 fatty acids) on regional blood flow during low-dose Escherichia coli endotoxin infusion (0.1 mg/100 g body weight [BW]) in a rat model. Despite absence of changes in the cardiac output, blood flow rates to the small and large intestines, stomach, and pancreas, and also to the skin and skeletal muscle were significantly reduced after 18 hours of endotoxin infusion in the rats fed standard vegetable oil. Short-term IV feeding during a period of 40 hours with an isonitrogenous, isocaloric nutrient solution containing fish oil as the only lipid source normalized intestinal perfusion and increased blood flow to the liver and spleen. Low-dose endotoxin infusion also resulted in significant increases in glucose, lactate, and pyruvate concentrations. In comparison to standard vegetable fat emulsion, fish oil significantly reduced these parameters. A second experiment was conducted to measure lactate kinetics. Based on the dilution of U-14C-lactate, fish oil feeding was associated with higher lactate clearance than standard vegetable oil feeding during the endotoxin infusion. We conclude that short-term IV feeding with fish oil improves intestinal perfusion and portal blood flow, improves glucose tolerance, and increases lactate clearance in a low-dose endotoxin rat model.