Journal of the American College of Nutrition, Vol. 21, No. 4, 351-356 (2002)
Published by the American College of Nutrition
Endotoxin-Mediated Hepatic Lipid Accumulation During Parenteral Nutrition in Rats
Roland N. Dickerson, PharmD, FACN and
Claudia B. Karwoski, PharmD
The University of Tennessee Health Sciences Center, Memphis, Tennessee
Address correspondence to: Roland N. Dickerson, PharmD, Department of Pharmacy, University of Tennessee Health Sciences Center, 26 South Dunlap St., Memphis, TN 38163
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ABSTRACT
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Objective: To assess the effect of endotoxemia on hepatic lipid content during parenteral nutrition (PN) in rats.
Methods: Twenty male Sprague-Dawley rats (185–230 gm) were randomized to receive PN (n=9) or PN plus a continuous infusion of E. coli 026:B6 lipopolysaccharide (LPS; n=11). All animals received isocaloric (170 kcal/kg/day), isonitrogenous (1.1 g N/kg/day), glucose-based PN for the next 78 hours. After 30 hours of adaptation to TPN, the animals were randomized to receive PN or PN plus LPS at 6 mg/kg/day for the remaining 48 hours of study. The animals were euthanized and the livers were harvested.
Results: Liver weight increased significantly (by 60%) from 7.5 ± 0.6 g to 12.1 ± 2.4 g (p 
0.01) in the animals who received PN versus LPS, respectively. The proportion of liver water remained the same for PN and LPS groups (72.9 ± 3.2% versus 72.3 ± 3.8%, respectively, p = N.S.). However, liver fat increased disproportionately (by about 130%) from 0.20 ± 0.05 g to 0.46 ± 0.20 g (p 0.01) total fat weight or from 9.6 ± 1.8% to 13.6 ± 4.1% (p 0.02) lipid content (g/g) of the dry liver weight for the PN and LPS groups, respectively.
Conclusion: Endotoxin, when given concomitantly with parenteral nutrition, increases hepatic lipid accumulation and thus augments the development of parenteral nutrition-associated fatty liver in rats.
Key words: parenteral nutrition, endotoxin, lipopolysaccharide, cholestasis, liver disease, rat
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INTRODUCTION
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Since the introduction of total parenteral nutrition in the late 1960’s, parenteral nutrition therapy has become an integral part of the management of hospitalized patients who cannot use the gastrointestinal tract for a prolonged period of time. However, parenteral nutrition has its own inherent and associated complications such as liver dysfunction [1]. Parenteral nutrition-associated liver dysfunction in adults classically presents as a fatty infiltration of the liver or a non-specific triaditis usually resulting in a cholestatic jaundice [1–4]. Although fatty infiltration of the liver is generally considered a complication of parenteral nutrition when glucose or fat calories are given in excess [4–7], the presence of inflammation or infection has been suggested to augment hepatic lipid accumulation in some patients [3,8–10].
The purpose of this investigation was to ascertain if the continuous intravenous administration of endotoxin, which contributes to some of the detrimental effects of sepsis and inflammation, would result in increased hepatic lipid accumulation during parenteral nutrition.
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MATERIALS AND METHODS
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Twenty adult male Sprague-Dawley rats (Harlan, Inc., Indianapolis, IN) weighing between 190 and 230 g were included for study. This study was approved and conducted according to the guidelines of the Institutional Animal Care and Use Committee. Three days prior to cannulation, the animals were placed in individual metabolic cages in a controlled temperature environment (23°C) with a twelve hour light-dark cycle. The animals were maintained on a fiber-free, high-carbohydrate, low fat liquid diet (SLD, Ross Laboratories, Columbus, OH) at 160 kcal/kg/day and 1.4 g/kg/day of nitrogen with water ad libitum in an effort to standardize any influence of enteral nutritional intake upon hepatic triglyceride synthesis [11]. On the fourth day, the animals were anesthetized with ketamine and xylazine (87/13 mg/kg by intraperitoneal injection), and a chronic superior vena cava cannula was placed via the right external jugular vein as previously described [12]. Post-operatively, animals were maintained nil per os except for water ad libitum. Immediately after cannulation, the animals received an infusion of normal saline at 1.2 ml/hour via the central venous catheter to permit recovery from the anesthesia. Following a recovery period, the animals received isocaloric, isonitrogenous, isovolumetric parenteral nutrition (170 kcal/kg/day, 1.1 g/kg/day of nitrogen, and 140 ml/kg/day) for the next 78 hours. The dosage of nutrients was based on the National Research Council guidelines for maintenance energy and protein requirements of adult rats [13]. The parenteral nutrition solution contained sterile dextrose, amino acids, water, electrolytes, trace minerals and vitamins as described in Table 1.
After 48 hours of recovery post-cannulation and tether placement and adaptation to continuous parenteral nutrition, the animals were randomly assigned to either a control or endotoxin group. The control group received only parenteral nutrition (PN). The endotoxin group (LPS) received parenteral nutrition plus a continuous intravenous infusion of E. coli 026:B6 lipopolysaccharide (Sigma, St. Louis, MO) at 6 mg/kg/day for the final 48 hours of the study. We selected a continuous intravenous endotoxin infusion model for study as the animals emulate the protein catabolic and clinical features similar to sepsis [14–17]. Our previous work indicated that the dosage of this strain of lipopolysaccharide was optimal as the animals had increased urinary nitrogen and 3-methylhistidine excretion, decreased urine output, piloerection, serous exudate around the eyes and nose and abnormal feeding behavior [14–19]. Forty-eight hours of endotoxin infusion was selected as the maximum window for study since tolerance to the metabolic effects of endotoxin begin after 48 hours in rats [20]. At the end of the study, the animals were euthanized by exsanguination via the jugular venous catheter while anesthetized and the blood was collected for subsequent analyses. Following collection of blood, the entire liver was rapidly excised and weighed.
Serum aspartate aminotransferase (AST) and alkaline phosphatase concentrations were determined by a spectrophotometric kinetic assay. Serum total bilirubin and direct bilirubin concentrations were performed using a modified dimethyl sulfoxide spectrophotometric assay. Serum albumin concentration was determined by bromcresol green binding assay. All serum chemistry assays were conducted using diagnostic kits from Sigma Diagnostics (St. Louis, MO). Liver composition was determined from a modification of the method of Jacobs [21]. Liver water content was determined gravimetrically by vacuum dessication at 90°C. Liver fat content was determined by chloroform and methanol extraction [22]. Liver nitrogen was determined by the micro-kjeldahl technique [23].
Continuous data were expressed as mean ± S.D. The Kolmogorov-Smirnov test for normality was used to ascertain if the data varied significantly from the pattern expected if the data was drawn from a population with a normal pattern. Data were analyzed by the t test for unpaired variables or by the Mann-Whitney U test for data without a normal distribution. Nominal data were analyzed using the Fisher Exact Probability test. The correlation of two variables was conducted using the Pearson Product Moment Correlation Coefficient. A probability value equal to or less than 0.05 was defined as significantly different.
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RESULTS
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There was no significant difference in preoperative weight, energy and nitrogen intakes, or survival rates between groups as summarized in Table 2. One of the LPS animals expired during the study. Both groups lost a small amount of weight; however, weight loss was significantly greater in the LPS group (Table 2). Serum albumin was significantly lower in the LPS group compared to PN control at the end of the infusion period (Table 3). Serum markers of liver injury (AST, total bilirubin, direct bilirubin, alkaline phosphatase) tended to be higher for the LPS group; however, these trending differences were not statistically significant (Table 3).
Table 4 provides the changes in liver composition that occurs in rats given continuous endotoxin infusion in addition to parenteral nutrition. Administration of LPS resulted in an increase in liver weight by 61% (p 0.01). The amount of water, total nitrogen and total fat also significantly increased in response to LPS (Table 4). However, the proportion of liver water weight for the PN and LPS groups remained unchanged at 72% and 73%, respectively (p = N.S.). The amount of liver fat increased disproportionately by about 130% in the LPS group (p 0.01; Table 4). Total lipid content of the dry liver weight for the LPS group significantly increased by about 40% compared to PN control (p 0.02; Table 4). Liver fat content, when normalized to mg/g of wet or dry liver weight, was significantly increased by the administration of endotoxin. Liver fat content increased from 21 mg to 32 mg/g of wet liver weight (p 0.05) and increased from 76 mg to 115 mg/g of dry liver weight (p 0.01) in the PN and LPS groups, respectively, as illustrated in Fig. 1. There were no significant correlative relationships between serum concentrations of aspartate aminotransferase, total bilirubin, direct bilirubin, or alkaline phosphatase and fat content of the liver.
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Fig. 1. Comparison of accretion of liver fat in the PN control and LPS rats expressed in mg of fat per gram of liver tissue. Data are given as mg of fat per gram of dry liver weight on the left and mg of fat per gram of wet liver weight shown on the right. *p < 0.01, **p < 0.05.
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DISCUSSION
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Parenteral nutrition-associated liver dysfunction appears to be a complex, multifactorial process and is commonly attributed to excessive glucose, lipid, or total caloric intake often in the absence of oral intake [2–6,8,9,24,25]. This complication is of particular concern as it may not always be reversible [1]. Parenteral nutrition-associated liver dysfunction also appears to be accentuated by the presence of inflammation and infection [3,8–10] which may be a complication of the patients’ primary disease process. Our data indicates that the administration of endotoxin, a substance that contributes to the detrimental aspects of inflammation and infection, results in a marked accumulation of hepatic fat during parenteral nutrition. The amount of fat content in the livers of animals exposed to intravenous endotoxin was significantly greater than the amount of liver fat gained in rats receiving parenteral nutrition without endotoxin (Table 4 and Fig. 1).
Liver dysfunction associated with short-term parenteral nutrition in adults is often reversible upon discontinuation of the parenteral nutrition in contrast to development of liver dysfunction associated with long-term parenteral nutrition in patients with chronic inflammation and immune activation which may be fatal [1,10]. Parenteral nutrition-associated liver dysfunction is an undesirable event in the short-term parenterally-fed critically ill patient experiencing multiple organ dysfunction syndrome. Our endotoxemia model probably most closely emulates the parenterally-fed, critically ill patient [14–18,26]; however, it may also share some similarities to the long-term patient with sustained inflammation and immune activation. Parenteral nutrition-associated liver dysfunction is typically associated with prolonged overfeeding. In an effort to avoid overfeeding the animals with parenteral nutrition, we intentionally provided a conservative caloric regimen that was designed to emulate weight maintenance of orally fed adult rats based of the National Research Council guidelines [13]. This parenteral nutrition regimen, providing 170 kcal/kg/day and 1.1 g/kg/day of nitrogen, resulted in a 2% to 3% weight loss in the control PN-fed rats. As anticipated, the LPS group had a significantly greater weight loss (
5% total; Table 2) due to the hypermetabolic-hypercatabolic response to the endotoxin infusion [14–17]. This caloric intake was lower than that given to rats in other studies that provided 250 to 360 kcal/kg/day to investigate parenteral nutrition-associated liver dysfunction [8,9,27–32]. Our parenterally fed animals had similar amounts of total liver fat when compared to other rats given 100% of their "ad libitum oral intake" via parenteral nutrition [7] (21 mg of total fat per gram of wet liver tissue versus 25 mg of triglyceride per gram, respectively) and had less liver fat than other standard diet control animals prior to initiation of parenteral nutrition [33] (21 versus 45 mg/g wet tissue, respectively). The LPS animals in our study gained substantial liver fat similar to those animals who were overfed at 200% of "ad libitum intake" (32 mg of total fat per gram versus 28 mg of triglyceride per gram, respectively) [7]. Comparison of our results with data derived in these other studies suggests a minimal effect of our parenteral nutrition regimen upon liver lipid content when unstressed rats are fed a weight-conservative regimen, whereas LPS animals significantly gained liver fat similarly to animals markedly overfed by parenteral nutrition. Although accumulation of liver fat often parallels appearance of oil droplets in hepatic morphologic studies, our study is limited by lack of histopathologic comparisons which could have elucidated evidence of liver tissue damage or hepatic fatty infiltration in the LPS-treated animals receiving parenteral nutrition.
The etiology of parenteral nutrition-associated liver dysfunction is multi-factorial. In the absence of overfeeding, it has been suggested that the inflammatory process (often associated with sepsis or systemic inflammatory response syndrome) is the most important predisposing event leading to the development of cholestasis in patients receiving short-term parenteral nutrition [3,8,28,29,34]. Lipopolysaccharide is known potent inducer of tumor necrosis factor production as well as production of other cytokines [35]. These cytokines cause an increase in albumin catabolism, extravasation from the intravascular space and a decrease in albumin synthesis [36]. A significantly lower serum albumin in the LPS versus PN control group (Table 3), along with the observed clinical symptomatology of endotoxemia in the animals, provides evidence of an acute inflammatory state in the LPS group. Cytokines have been implicated as causative agents in the development of hepatic dysfunction during multiple system organ failure. Interleukin-1 significantly depressed bile flow in the isolated perfused rat liver [37] and tumor necrosis factor stimulated hepatic lipid synthesis and secretion in rats [38]. Others have shown that the administration of monoclonal antibodies to tumor necrosis factor has resulted in less PN-associated liver dysfunction in unstressed, parenterally-fed rats [27]. Therefore, it is unclear whether the increase in the accumulation in liver fat during combined endotoxemia and parenteral nutrition as compared to PN alone is due to the administration of lipopolysaccharide, the cytokine inflammatory response created by lipopolysaccharide or a combination of factors.
The characteristic rises in serum hepatic enzymes concentration associated with cholestatic liver disease from parenteral nutrition-associated liver dysfunction were not clearly evident in this study. Although serum levels of alkaline phosphatase, total bilirubin, direct bilirubin and aspartate aminotransferase were slightly higher in the LPS group compared to control, differences between groups were not statistically significant (Table 3). Sax and coworkers found that fatty infiltration of the liver from excessive overfeeding with parenteral nutrition occurred independently of any changes in serum hepatic enzyme concentrations in rats [8]. Therefore, it was not particularly surprising that there was no correlation between elevations in serum hepatic enzyme concentrations and fat content of the liver.
Omission of an enterally-fed control group and enterally-fed LPS group may be considered a limitation of this study. These groups could have differentiated the effect of parenteral versus enteral nutrition upon hepatic lipid accumulation in response to endotoxemia. However, providing hypertonic parenteral nutrition by gastrostomy during endotoxemia in rats is difficult. A previous attempt in a small pilot study by our laboratory resulted in significant gastrointestinal intolerance and aspiration events of the endotoxemic rats (unpublished observations). Although useful, a comparison of enteral nutrition versus parenteral nutrition during endotoxemia upon hepatic lipid accumulation was beyond the scope of this study. Another potential limitation of this study is the provision of a glucose-amino acid parenteral nutrition solution. Providing a parenteral nutrition solution devoid of lipid may predispose the animals to developing essential fatty acid deficiency which can lead to hepatic steatosis [33]. Adult rats require an extensive period of starvation, then refeeding of a lipid-free diet in order to develop signs of essential fatty acid deficiency [13]. However, Kiem and Mares-Perlman [33] found evidence of hepatic essential fatty acid deficiency after four days of overfeeding of a glucose-based, lipid-free, parenteral nutrition at 350 nonprotein kcals/kg/day (over twice the glucose intake given in our study) in rats. It is unknown whether the animals in our study developed biochemical evidence of essential fatty acid deficiency as fatty acid profiles (triene:tetraene ratio) were not examined. It is unlikely that significant hepatic steatosis due to fatty acid deficiency occurred in our animals given the amount of liver fat content. Additionally, others have shown that rats treated with a low calorie, lipid-free parenteral nutrition regimen do not have hepatic fatty infiltration [8,9,31]. Our data indicates the presence of endotoxemia significantly worsens hepatic fat accumulation even when a conservative parenteral caloric intake is given.
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CONCLUSION
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Infection and inflammation have been suggested to augment hepatic lipogenesis associated with parenteral nutrition. Endotoxemia contributes to some of the detrimental effects of sepsis and inflammation. In our study, liver fat increased disproportionately (by 130%) compared to the increase in liver weight (60%) in animals given lipopolysaccharide. Fat content of the livers from the endotoxemic animals was significantly greater than the liver fat content of parenterally fed controls. Our data indicate that endotoxin, when given concomitantly with parenteral nutrition, increases hepatic lipid accumulation and thus augments the development of parenteral nutrition-associated fatty liver. Although development of parenteral nutrition-associated hepatic dysfunction in rats may not completely represent the conditions observed in humans, the results derived from these animal models can give further insight into clinical investigations.
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ACKNOWLEDGMENTS
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The assistance of Jean-Jacques Rajter, B.A. and R. Gregg Settle, Ph.D. is acknowledged. This study was supported in part by a Veterans Affairs Merit Review Grant (R.G.S.) and by an Academic Research Enhancement Award (R.N.D.) from the Public Health Service (1R15DK46545-01). The amino acids (FreAmine IIITM), trace minerals and intravenous nutrient bags were kindly donated by B Braun, Inc. (Irvine, CA).
Received May 24, 2001.
Accepted January 2, 2002.
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ABSTRACT
INTRODUCTION
