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Article

Dietary Stearic Acid Reduces Cholesterol Absorption and Increases Endogenous Cholesterol Excretion in Hamsters Fed Cereal-Based Diets^{1 ,2}

Department of Nutritional Science and Dietetics, University of Nebraska, Lincoln, NE 68583-0806

³To whom correspondence should be addressed.

	ABSTRACT

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The observation that dietary stearic acid does not raise plasma cholesterol concentration is well documented, although the regulating mechanisms are not completely understood. Therefore, we examined the effect of dietary stearic acid on cholesterol absorption and sterol balance using male Syrian hamsters fed modified NIH-07 cereal-based diets selectively enriched in palmitic acid (16:0), stearic acid (18:0), trans fatty acid (18:1t), cis oleic acid (18:1c) or linoleic acid (18:2). All diets contained 17 g/100 g total fat and 0.05 g/100 g cholesterol; the five fat blends were enriched 30% with the fatty acid of interest above a constant fatty acid background. Cholesterol absorption efficiency was 50–55% in all treatment groups except for the 18:0 group, in which cholesterol absorption was significantly reduced to 21%. Plasma total cholesterol concentration was significantly lower in the 18:0 group compared to the 16:0 group. Fecal neutral steroid excretion was significantly greater in hamsters fed the high 18:0 diet compared to the other treatment groups. After accounting for unabsorbed dietary cholesterol, endogenous cholesterol excretion was about 100% higher in the 18:0 group. Consequently, the calculated rate of whole body cholesterol synthesis was significantly increased by dietary 18:0. Bile acid excretion accounted for only 12–20% of total sterol output by the hamsters in this study. Thus, the data suggest that reduced plasma cholesterol concentration in hamsters fed high 18:0 diets may be influenced by reduced cholesterol absorption and increased excretion of endogenous cholesterol.

KEY WORDS: • stearic acid • sterol balance • cholesterol absorption • hamsters

	INTRODUCTION

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Early studies by Ahrens et al. (1957) , Keys et al. (1965) and Hegsted et al. (1965) clearly showed stearic acid (18:0)⁴ to be unique among the saturated fatty acids commonly found in the food supply because it did not raise plasma cholesterol concentration. Several human and animal studies have since been conducted confirming the "neutral" or hypocholesterolemic effect of dietary 18:0 (reviewed by Grundy 1994 ). Despite these observations, little is known about the mechanisms whereby 18:0 regulates cholesterol metabolism.

Studies in rats (Feldman et al. 1979a and 1979b ) have suggested that dietary 18:0 inhibits cholesterol absorption. A reduction in cholesterol absorption could lead to changes in sterol balance and cholesterol turnover. Consequently, the present study was conducted to examine the role of 18:0 and other common dietary fatty acids in cholesterol absorption and turnover using the hamster model. A novel aspect of the study was the use of five experimental diets differing in only a single fatty acid, which allowed the isolation of specific metabolic effects of each fatty acid. We chose to focus on five fatty acids commonly found in the U. S. food supply: palmitic acid (16:0), stearic acid (18:0), trans fatty acids (18:1t), cis oleic acid (18:1c) or linoleic acid (18:2).

	MATERIALS AND METHODS

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Animals and diets.

Male Syrian hamsters (Charles River, Wilmington, MA) weighing ~70 g were individually housed in polycarbonate cages with a bedding of wood chips. Hamsters were kept in an environmentally controlled room at 25°C with a 12-h light-dark cycle for the duration of the 18-wk experiment. All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Nebraska.

Hamsters were fed a modified version of the NIH-07 open-formula, cereal-based rodent diet (AIN 1977 , Knapka et al. 1974 ). We have recently published a more thorough discussion on the usefulness of the modified NIH-07 diet in hamster studies (Cai and Carr 1999 ). The primary modification was an increase in total fat from 25 to 150 g/kg diet, with compensatory decreases in ground corn, ground wheat and wheat middlings (Table 1 ). The grains and fish meal used in the modified NIH-07 diets contained some residual fat and, thus, contributed a minimal amount of fat (~2 g/100 g) to the total diet composition. Cholesterol was also added to the diets to achieve a concentration of 0.05 g/100 g. The diets were prepared by Dyets (Bethlehem, PA) using oil blends supplied by our laboratory. Five experimental diets were made with several different vegetable oils so that each diet was enriched in a single fatty acid (Table 2 ). Each oil blend was enriched 30% with the fatty acid of interest above a constant fatty acid background made up of ~10% 16:0, 8% 18:0, 0% 18:1t, 40% 18:1c and 8% 18:2.

The amount of tocopherols in the oil blends was measured by HPLC (Ueda and Igarashi 1987 ). The high 18:2 oil blend contained the highest amount of tocopherols; therefore, (+)--tocopherol acetate was added to the other oil blends to produce the same -tocopherol equivalents in each oil blend.

Experimental design.

Hamsters (n = 64) were randomly divided into five groups. Each group contained 13 animals except the 18:0 group, which contained 12 animals. Hamsters were fed for 18 wk and were given free access to their diets and water supply. Body weights were recorded bi-weekly and food intake was recorded weekly during the 18-wk study. Body weight and food intake are expressed as the average of measurements taken between wk 12 and 18 (Table 3 ). We have expressed the data in this manner because a single value for body weight, food intake and fecal output was needed for calculating the sterol balance data shown below. We chose to average data from wk 12–18 because weekly food intake measurements were not significantly different during this period and the hamsters were no longer growing. In addition, fecal output and subsequent fecal lipid analyses were performed on samples collected during wk 12, whereas plasma cholesterol measurements were made in samples collected during wk 18. Therefore, we wanted body weight and food intake to reflect the entire period between wk 12 and 18.

Cholesterol absorption efficiency.

Cholesterol absorption was measured during wk 8 by simultaneous oral administration of [³H]-ß-sitostanol and [¹⁴C]-cholesterol (Borgström 1968 ). ß-Sitostanol virtually is not absorbed in the intestinal tract of hamsters (Turley et al. 1994 ); thus it serves as a reference compound for cholesterol absorption. The radiolabeled sterols were purchased from American Radiolabeled Chemicals (St. Louis, MO). Hamsters were dosed on two consecutive days with 50 µL vegetable oil containing ~80 kBq [³H]-ß-sitostanol and 80 kBq [¹⁴C]-cholesterol. They were allowed to ingest the radioisotope/vegetable oil mixture via eyedropper while still in their cages, so essentially no stress was incurred during the procedure. Feces were collected, finely ground and saponified, and total radioactivity was quantified by scintillation spectrometry as previously described (Cai and Carr 1999 ). Cholesterol absorption efficiency was calculated as a percentage from the ratio of the two radiolabels in the dose and feces using the following equation: Percenage cholesterol absorption = [(¹⁴C/³H in dose -¹⁴C/³H in feces)/(¹⁴C/³H in dose)] x 100.

Fecal neutral steroids.

Nonradioactive feces (~50 mg) were extracted into methanol/chloroform (2:1, v/v) (Folch et al. 1957 ) containing 10 mg/L 5-cholestane as an internal standard. Prior to lipid extraction, the fecal samples were acidified by adding 0.2 mL of 0.5 mol/L HCl. The lower phase solvent was evaporated and the samples saponified in 2 mL 1 mol/L methanolic KOH for 1 h at 50°C. After the addition of 2 mL deionized water, the nonsaponifiable lipids were extracted into 5 mL hexane. The hexane was evaporated under nitrogen and the steroids derivatized by adding 100 µL pyridine, followed by 50 µL Sylon BTZ (Supelco, Bellefonte, PA). The samples were allowed to stand 30 min at room temperature and the reaction was stopped by placing the samples on ice. The fecal neutral steroids were quantified by gas chromatography using a 0.25 mm x 15 m DB-1 capillary column (J & W Scientific, Folsom, CA) under the following conditions: initial temperature 190°C for 1 min, increased to 220°C at 3°C/min; injector temperature, 270°C; flame ionization detector temperature, 300°C; helium carrier gas; and split ratio of 50:1. Sterols of plant origin were identified but were not included in the analysis. Fecal "neutral steroids" reported herein refer to the sum of cholesterol, dihydrocholesterol, coprostan-3-one and coprostan-3-ol.

Fecal bile acids.

Ground feces (~100 mg) were placed in screw-cap tubes with 0.7 mL deionized water; 10 mL chloroform/methanol (2:1, v/v) was added according to the method of Folch et al. (1957) . After 30 min, 2 mL 8.8 g/L KCl was added and mixed, and the sample was centrifuged at 1000 x g for 15 min to separate phases. The upper phase containing bile acids was quantitatively transferred to a clean tube and the lower phase was washed once by adding fresh upper phase (chloroform/methanol/water, 3:48:47). The sample was gently mixed and centrifuged as before. The upper phase from the wash step was added to the upper phase from the first extraction. An aliquot of upper phase was transferred to a 1-cm diameter round cuvette and the solvent was evaporated at 50°C under a stream of nitrogen.

Total bile acids in the cuvette were quantified by first dissolving the bile acids in 0.1 mL methanol. Exactly 3.5 mL incubation buffer was added to the samples and mixed. The incubation buffer contained 0.2 mg ß-NAD (Sigma Chemical, St. Louis, MO) per mL of 0.05 mol/L CAPS buffer (pH 10.8) and was prepared immediately prior to use. The background absorbance of the samples was determined at 340 nm. The reaction was initiated by adding 0.4 mL 3-hydroxysteroid dehydrogenase (750 U/L 0.01 mol/L phosphate buffer, pH 7.2). Hydroxysteroid dehydrogenase was purchased from Sigma Chemical. The samples were incubated at 37°C for 30 min. The absorbance was read again at 340 nm to determine the concentration of NADH. The concentration of total bile acids was calculated by the difference of the two absorbance readings (accounting for the dilution of 0.4 mL enzyme solution), compared against a calibration curve using cholic acid standards in methanol.

Dietary lipid absorption.

Dietary lipid absorption was measured as the difference between the amount of lipid consumed and the amount excreted. Diet and fecal lipids were extracted from oven-dried samples into chloroform/methanol (2:1, v/v) according to the method of Folch et al. (1957) . The extraction solvent was evaporated and the amount of lipid in the diets and feces was determined gravimetrically. Total fecal lipid values were adjusted by subtracting out the amount of neutral steroids present in the feces to more accurately quantify saponifiable fecal lipids. The absorption of individual fatty acids was also quantified by determining the fatty acid distribution in fecal lipids using the same procedure described above for dietary fatty acids.

Plasma cholesterol.

Blood was collected by cardiac puncture using 10 mL syringes containing 10 mg EDTA as an anticoagulant. Red blood cells were removed by centrifuging the blood at 1000 x g for 30 min at 4°C. Plasma (~2–3 mL) was recovered from each hamster. Aprotinin (1 mg/L) and phenylmethylsulfonyl fluoride (80 mg/L) were added to the plasma as preservatives. Plasma total cholesterol concentration was determined enzymatically (Carr et al. 1993 ).

Statistical analyses.

Treatment and time effects were statistically analyzed using ANOVA. Differences among treatment groups were assessed by the Tukey multiple comparison procedure. Differences with P < 0.05 were considered significant. Associations between variables were determined by Pearson product moment correlation analysis. All statistical analyses were performed on a personal computer using SigmaStat (SPSS Science, Chicago, IL).

	RESULTS

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The body weight of hamsters at the beginning of the study was ~70 g, which increased to maximum body weight by wk 10. The mean body weights recorded between wk 12 and 18 are shown in Table 3 . Body weight of hamsters fed the high 18:0 diet was significantly lower compared to the 18:1c and 18:2 groups. Fecal output was significantly higher in the 18:0 group compared to hamsters fed diets high in 16:0, 18:1t and 18:2 (Table 3) . Plasma total cholesterol concentration was significantly lower in hamsters fed the 18:0 diet compared to hamsters fed the 16:0 diet (Table 3) .

Food intake, recorded weekly throughout the study, was not significantly different among treatment groups at any of the time points (data not shown). Food intake was highest early in the study while the hamsters were still growing (54–59 g/wk at wk 3), and decreased to 37–42 g/wk by wk 12. Food intake was not significantly different in any of the treatment groups between wk 12 and 18, and the mean food intake during this period is shown in Table 3 .

Total dietary lipid absorption (mg/d) was significantly less in the 16:0 and 18:0 groups compared to hamsters fed diets high in 18:1t, 18:1c and 18:2 (Table 4 ). When expressed as a percentage of dietary lipid absorbed, total lipid absorption was ~93–94% in all treatment groups except for hamsters fed the high 18:0 diet, in which lipid absorption efficiency was significantly less at 89%. Table 4 also shows the absorption of individual dietary fatty acids. In general, the saturated fatty acids were absorbed less efficiently than the unsaturated fatty acids in all treatment groups.

Daily cholesterol absorption and excretion, normalized to body weight, is shown in Table 6 . Cholesterol absorption efficiency was significantly reduced in hamsters fed the high 18:0 diet compared to the other treatment groups. Dietary cholesterol mass absorbed (calculated by multiplying the fractional absorption with total cholesterol intake) was also significantly lower in the 18:0 group compared to the other treatment groups. Consequently, the mass of dietary cholesterol not absorbed was significantly higher in the 18:0 group. Endogenous cholesterol excretion was then calculated by subtracting the amount of unabsorbed dietary cholesterol from total neutral steroids in the feces. Endogenous cholesterol excretion was significantly higher in hamsters fed the high 18:0 diet compared to the other treatment groups. Thus, total cholesterol turnover (endogenous cholesterol + bile acid excretion) was about 100% higher in the 18:0 group (11 µmol x d^-1 x 100 g body wt^-1) compared to the other treatment groups (5–6 µmol x d^-1 x 100 g body wt^-1).

	DISCUSSION

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We included 18:1t in the study design because of the recent claim that consumption of trans fatty acids causes 30,000–150,000 deaths each year from heart disease (Food Chemical News 1994 , Willett and Ascherio 1994 ). Contrary to our initial hypothesis, dietary 18:1t was not hypercholesterolemic, and no significant differences were observed in cholesterol absorption efficiency or cholesterol turnover in the 18:1t group compared with hamsters fed diets enriched in 16:0, 18:1c and 18:2. Nicolosi et al. (1998) also reported no difference in plasma cholesterol concentration between hamsters fed diets enriched in 18:1t and 18:1c. In contrast, dietary 18:0 in the present study resulted in lower plasma cholesterol concentrations, significantly reduced cholesterol absorption and increased cholesterol turnover compared to the other treatment groups.

The increased cholesterol turnover in hamsters fed the high 18:0 diet was primarily due to increased fecal excretion of endogenous cholesterol. Although bile acid excretion was increased in the 18:0 group, endogenous cholesterol excretion accounted for 80–88% of total steroid output by the body. Imaizumi et al. (1993) also reported increased excretion of endogenous cholesterol in hamsters fed cholesterol-free diets enriched in 18:0 compared to diets high in 16:0, myristic (14:0) and lauric (12:0) acids. As in our study, bile acid output represented only 10–25% of total steroid excretion (Imaizumi et al. 1993 ). Addition of 0.2% cholesterol to the same fatty acid-enriched diets also resulted in increased neutral steroid excretion, but the contribution of unabsorbed dietary cholesterol to total fecal neutral steroids was not determined (Imaizumi et al. 1993 ). A similar finding was reported in rats fed cholesterol-free diets; fecal cholesterol excretion was increased in rats fed high 18:0 compared to 16:0 (Kamei et al. 1995 ). Bile acid excretion in the rats constituted a higher proportion of total steroid output than in hamsters (about 40% of total fecal steroids in the rat study), although no treatment differences in bile acid excretion were detected (Kamei et al. 1995 ).

Whether dietary 18:0 increases endogenous cholesterol excretion in humans is uncertain. Historically, sterol balance studies in humans were designed to compare "saturated" (e.g., coconut oil, butter) vs. "polyunsaturated" fats (e.g., corn oil, safflower oil) rather than isolating the effects of individual dietary fatty acids. While not all of the early sterol balance studies showed treatment effects, several studies demonstrated an increase in neutral steroid excretion when polyunsaturated fats replaced saturated fatty acids in the diet (Antonis and Bersohn 1962 , Connor et al. 1969 , Grundy 1975 , Moore et al. 1968 , Nestel et al. 1973 and 1975 , Shepherd et al. 1980 ). In the study of Connor et al. (1969) , corn oil was used as the polyunsaturated fat and cocoa butter as the saturated fat source. Although cocoa butter contains about 35% 18:0, it also contains 25–26% 16:0. The multiple fatty acid differences in the plant oils used by Connor et al. (1969) did not allow the investigators to isolate the contribution of dietary 18:0 to endogenous steroid excretion.

Hamsters fed the high 18:0 diet had lower body weights than hamsters in the other treatment groups despite similar food intakes. To account for the differences in body weight, the sterol balance data in this report have been normalized to 100 g body weight. Kamei et al. (1995) also reported that hamsters fed diets high in 18:0 compared to 16:0 had decreased body weight gain. Nicolosi et al. (1998) reported decreased body weight gain and feed efficiency in hamsters fed diets enriched with 18:0 compared to caprylic acid (8:0), 14:0, 18:1c and 18:1t. In both studies (Kamei et al. 1995 , Nicolosi et al. 1998 ), as in the current study, lipid absorption was also decreased in animals consuming 18:0 enriched diets. The present data suggest that decreased absorption of total energy from fat may account for the decrease in body weight in hamsters fed the high 18:0 diet. A significant correlation (r = 0.79, P < 0.001) was observed between the amount of dietary lipid absorbed (Table 4) and body weight (Table 3) when individual animal data points were plotted. A correlation of the means of lipid absorption and body weight showed a stronger correlation (r = 0.99, P < 0.001). These data, however, do not exclude the possibility that the high 18:0 diet may have limited the absorption of other nutrients necessary for optimal growth.

Reduced cholesterol absorption in the 18:0 group likely contributed to the significant increase in endogenous cholesterol excretion. Studies in lymph duct cannulated rats fed 18:0-enriched diets showed a significant reduction in cholesterol absorption (Chen et al. 1989 , Ikeda et al. 1994 ). Using three different methods to measure cholesterol absorption (i.e., plasma isotope ratio method, fecal dual isotope method and lymph duct cannulation), Feldman et al. (1979a and 1979b ) clearly documented reduced cholesterol absorption in rats fed 18:0. We were unable to find a human study that examined the specific effect of dietary 18:0 on cholesterol absorption. Nevertheless, the present study in hamsters provides evidence in a species other than rats that dietary 18:0 inhibits cholesterol absorption.

Schmidt and Gallaher (1997) suggested in a recent abstract that dietary 18:0 decreased cholesterol solubilization in the small intestine. We speculate that dietary 18:0 inhibits cholesterol absorption by interfering with micelle formation. Disrupted micelle formation could occur by several possible mechanisms. First, because 18:0 is a straight, long-chain fatty acid, its physical presence in the small intestine may impart micellar instability. However, 18:1t is similar to 18:0 in physical dimension but did not reduce cholesterol absorption in the present study, so this possibility seems unlikely. Second, dietary 18:0 incorporation into hepatic and biliary phospholipids could alter micelle formation. Wang and Koo (1993a and 1993b ) showed that 18:0 delivered to the liver was preferentially incorporated into phospholipids. Cohen and Carey (1991) reported that micelle stability and cholesterol solubility were reduced when micellar phospholipids contained 18:0 compared to unsaturated fatty acids. Third, dietary 18:0 incorporated into the liver could alter the bile acid profile and, consequently, the ability to solubilize cholesterol. Hassel et al. (1997) recently reported that dietary 18:0, relative to 16:0, significantly altered the fecal bile acid composition in hamsters. Preliminary data in our laboratory (Carr, T. P., unpublished observations) further indicate that dietary 18:0 alters the bile acid profile and thus decreases the "hydrophobicity index" (Heuman 1989 ) of the bile. A reduced hydrophobicity index of bile would presumably decrease cholesterol solubility and absorption. Fourth, the stereospecific composition of the dietary triacylglycerol molecules may also influence micelle formation. Sheanut oil and cocoa butter were used in this study as major sources of dietary 18:0. The triacylglycerol molecules present in cocoa butter and, presumably, sheanut oil contain 18:0 mainly in the external (sn-1 and sn-3) positions (Small 1991 ). The free 18:0 liberated during digestion is absorbed to a lesser extent than other common dietary fatty acids (reviewed by Bracco 1994 ), suggesting a decreased ability of free 18:0 to form stable micelles. Our current data (Table 4) also indicate lower 18:0 absorption. It is presumed that the high melting temperature of 18:0 contributes to its decreased solubility and absorbability (Small 1991 ). Consequently, impaired micelle formation due to the presence of dietary 18:0 would also inhibit the absorption of cholesterol in the small intestine.

Finally, it is important to discuss how cholesterol absorption and turnover might be related to plasma cholesterol concentration. The hypocholesterolemic effect of dietary 18:0 in humans is well documented (reviewed by Grundy 1994 ), and the plasma cholesterol concentration in the present study was lowest in hamsters fed 18:0-enriched diets. This finding appears to be attributable, at least in part, to the increased excretion of endogenous cholesterol. Increased cholesterol output by the liver could lead to decreased hepatic cholesterol concentrations. Studies have shown decreased liver cholesterol concentration in hamsters fed diets high in 18:0 relative to 16:0, 14:0 and 12:0 (Hassel et al. 1997 , Imaizumi et al. 1993 ). We have also observed reduced liver cholesterol concentration in hamsters fed 18:0 (Carr, T. P., unpublished observations). Brown and Goldstein (1986) clearly documented that reduced liver cholesterol concentration leads to increased clearance of plasma LDL cholesterol via LDL receptors. Woollett et al. (1992) reported that hamsters fed 18:0, relative to 16:0, had significantly increased hepatic LDL receptor activity and decreased plasma LDL cholesterol concentration. Although LDL receptor activity was not measured in the present study, the data suggest that reduced plasma cholesterol concentration in hamsters fed high 18:0 diets may be influenced by reduced cholesterol absorption and increased excretion of endogenous cholesterol.

	FOOTNOTES

 
¹ Supported by USDA National Research Initiative Competitive Grant 9601088 and the Nebraska Agricultural Research Division (Journal Series No. 12730).

² Presented in part at Experimental Biology ’98 [Schneider, C. L. and Carr, T. P. (1998) Dietary stearic acid reduces cholesterol absorption in hamsters. FASEB J. 12: A562].

⁴ Abbreviations used: 12:0, lauric acid; 14:0, myristic acid; 16:0, palmitic acid; 18:0, stearic acid; 18:1t, trans fatty acids; 18:1c, cis oleic acid; 18:2, linoleic acid.

Manuscript received August 12, 1999. Initial review completed November 1, 1999. Revision accepted January 10, 2000.

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