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© 2006 American Society for Nutrition J. Nutr. 136:2160-2166, August 2006

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

L-Rhamnose and Lactulose Decrease Serum Triacylglycerols and Their Rates of Synthesis, but Do Not Affect Serum Cholesterol Concentrations in Men1,2

Janet A. Vogt3, Katrin B. Ishii-Schrade3, Paul B. Pencharz3,4, Peter J. H. Jones5 and Thomas M. S. Wolever3,6,*

3 Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 4 The Hospital for Sick Children, Toronto, ON, Canada; 5 School of Dietetics and Human Nutrition, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada; and 6 Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada

* To whom correspondence should be addressed. E-mail: thomas.wolever{at}utoronto.ca.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Colonic short-chain fatty acids (SCFA) may affect hepatic lipid metabolism. Lactulose increases colonic acetate production, whereas L-rhamnose increases propionate. To test the effects of oral L-rhamnose and lactulose for 28 d on fasting concentrations and hepatic synthesis of lipids in humans, 18 men were administered 25 g/d of L-rhamnose, lactulose, or D-glucose for 4 wk in a partially randomized crossover design, with blood collected from fasting subjects on the first and last day of each period. Cholesterol and triacylglycerol (TG) synthesis rates were determined using deuterated water uptake rate over the last 24 h of each period. Postprandial blood lipids, and glucose and insulin were assessed in 11 subjects on d 28. Fasting serum cholesterol was unchanged; however, when expressed as a percentage change, TG were decreased, relative to baseline (P < 0.04), by L-rhamnose (–10%) and lactulose (–10%), compared with D-glucose, which increased serum TG (+11%). Net TG-fatty acid (TGFA) synthesis on d 28 was lower with L-rhamnose (2.42 ± 0.38 g/d) and lactulose (2.62 ± 0.35 g/d) than with D-glucose (2.96 ± 0.31 g/d, P < 0.01). We conclude that these results do not support a primary role for propionate in the cholesterol-lowering effect of soluble fiber. However, both lactulose and L-rhamnose lowered serum TG (expressed as a percentage change) and TGFA synthesis, compared with D-glucose, which increased them. Although these data are consistent with inhibition of TGFA synthesis by SCFA, other aspects of the metabolism of these sugars cannot be ruled out as putative agents of their TG-lowering effects.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Primary intervention strategies that lower total serum cholesterol decrease the risk of developing coronary heart disease (1,2). The cholesterol-lowering effect of soluble fiber may be mediated by colonic short-chain fatty acids (SCFA),7 such as acetate and propionate. Although acetate is a substrate for the synthesis of cholesterol and fatty acids (3–5), propionate may inhibit these processes (4,6,7). In isolated rat hepatocytes, physiological propionate concentrations inhibited tritium incorporation into fatty acids (4,8) and cholesterol (6,8), but supraphysiological propionate concentrations may be required to achieve the same degree of inhibition (9) in isolated human hepatocytes.

In vitro fermentation of L-rhamnose produces more propionate and less acetate than does lactulose (10); ingestion of L-rhamnose in humans raises serum propionate acutely (11) and chronically (12) compared with lactulose or D-glucose, whereas lactulose raises serum acetate (11). In humans, 20 g/d of oral lactulose for 2 wk raised fasting serum cholesterol in subjects compared with a control diet (13). However, the effects on human lipid metabolism of consuming a propionate-producing unabsorbable carbohydrate are not known. Therefore, our main objective was to determine whether consumption of such a carbohydrate would affect blood lipid levels. To this end, we measured the effect of 25 g/d of oral L-rhamnose, lactulose, or D-glucose for 4 wk on fasting lipids. Our secondary objective was to measure cholesterol and triacylglycerol-fatty acid (TGFA) synthesis on d 28 of each period, using the deuterium incorporation method. We hypothesized that lactulose would increase serum total and LDL-cholesterol compared with D-glucose, and L-rhamnose would attenuate these increases. We also hypothesized that L-rhamnose would decrease cholesterogenesis and TGFA synthesis, compared with lactulose.


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Subjects. Healthy men, 18–60 y old, were recruited from the University of Toronto campus, and through an advertisement in a local newspaper. Exclusion criteria included: 1) any disorder that influenced blood lipids; 2) use of blood pressure or lipid-lowering drugs; 3) a history of gastrointestinal problems; 4) use of any antibiotics within the previous 3 mo; or 5) fasting plasma cholesterol or TG >95th percentile or <5th percentile for their age (see Supplemental Table 1) (14). Two subjects dropped out during the first phase, citing difficulties adhering to the protocol. Two subjects withdrew after completing the first phase, citing work-related reasons. One subject moved to another city after completing the D-glucose and L-rhamnose trials. A total of 17 subjects completed all 3 phases: they were 36 ± 3 y old, (mean ± SEM); range, 20–59 y, with a BMI of 25.4 ± 0.7 kg/m2, range; 19.0–30.2).

This study was approved by the Human Subjects Review Committee at the University of Toronto. All subjects gave informed written consent.

    Diets. During study periods, the subjects' diets were self-selected for the first 3 wk; an individualized control diet was followed during wk 4, as previously described (12). Diets were analyzed as previously described (12). The self-reported total daily intakes for selected nutrients during wk 4, for each study period, are presented in Table 1. The mean daily energy intake from the 7-d diet records was 26% less (P < 0.002) than the estimated total energy expenditure (TEE), with all but 2 subjects reporting a lower energy intake than their estimated TEE. These results are similar to those found in normal-weight individuals living in industrialized countries (15,16).


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  		TABLE 1 Self-reported total daily intakes by men during wk 4 of each treatment period1

 
Compliance, as assessed by the changes noted on the wk-4 diet records returned at the end of each study period, and by the number of empty sugar vials returned, was considered excellent. The percentage of vials returned empty was 100% for the L-rhamnose and D-glucose periods, and 98.7% for the lactulose period.

    Study design. The study followed a semirandomized crossover design in which all subjects underwent three 28-d study periods, supplementing their dietary intake with 25 g/d of lactulose, L-rhamnose, or D-glucose. The first group of subjects, (n = 9), began the study in May and were randomly assigned to either lactulose or L-rhamnose. After a 3-mo washout period, they took part in the D-glucose study period. The day after the end of the D-glucose study period, 7 of these subjects began study period 3 during which they consumed the remaining unabsorbable sugar. The second group of subjects (n = 9) began the study in September, and consumed D-glucose in their first study period. The day after completing the D-glucose study period, they were randomly assigned to either lactulose or L-rhamnose for the second study period. After a 6-mo washout period, these subjects and 2 from the first group completed their final study period. Study periods were not conducted during summer or winter to avoid seasonal effects on serum cholesterol measurements (17,18).

Subjects were asked to maintain their usual level of exercise. A previously validated questionnaire, given on each test day, assessed the number of times per week subjects engaged in strenuous, moderate, and mild leisure time activities over the preceding 4 wk (19). This information was used to determine individual factors for physical activity level during the supplementation period. TEE was calculated by multiplying the resting energy expenditure (estimated using the FAO/WHO equations) by the factor determined for physical activity level (20). For the test days, a physical activity level factor of 1.5 was used for all subjects.

At the start of each study period, a baseline blood sample was collected from fasting subjects and they were given a 2-wk supply of L-rhamnose (BDH), lactulose (Inalco Pharmaceuticals), or D-glucose (Sigma-Aldrich Canada). Lactulose is a synthetic disaccharide, which is 99.0% pure, with lactose (0.5%), and galactose (0.5%) as impurities; L-rhamnose is 99.7% pure. Each 25-g aliquot of sugar was divided among 3 vials. Subjects were told to dissolve the contents of 1 vial in a hot drink at breakfast, lunch, and dinner. On d 15 of each study period, subjects came to the clinic to hand in empty vials, discuss any symptoms they were experiencing, and take the remaining 2-wk supply of sugar and their electronic scale and diet template.

On d 29, subjects came to the clinic at 0730 after an overnight fast. Blood samples were taken for analysis of serum lipid concentrations and deuterium enrichment of plasma water and lipids. Some of the subjects (n = 11) were also participating in another study protocol in which blood samples, urine, and a fecal sample were collected for SCFA analysis (12); this occurred at the same time as their participation in the present study. These subjects remained at the clinic for 12 h, and hourly blood samples were collected for measurement of plasma glucose, insulin, TG, FFA, and glycerol.

The 11 subjects that stayed at the clinic ate in the metabolic kitchen: breakfast at 0800, snack 1 at 1030, lunch at 1300, snack 2 at 1530, and dinner at 1800. They were given 15 min to eat each meal/snack. The test sugar was added to a hot drink (9 g at breakfast and 8 g at lunch and dinner). The 7 subjects who left the clinic were given a morning snack, lunch, and an afternoon snack, to be eaten 2.5, 5.0, and 7.5 h after breakfast, respectively. They were also given the second dose of test sugar, to be taken after 5 h, in a hot drink. They were told to engage in minimal physical activity during the ~9.5 h outside the clinic. They returned to the clinic for dinner and the final sugar dose at 10 h, and stayed there until 12 h.

On d 30, all subjects returned to the clinic, having consumed only deuterium-enriched drinking water since dinner on d 29. Blood samples for measurement of deuterium enrichment were collected from fasting subjects exactly 24 h after the predose sample.

    Test day food intake. On the 1st test day, each subject chose 3 meals and 2 snacks from a fixed menu; this food intake was replicated on subsequent test days, as reported previously (11,12). The mean test day food intake for all 18 subjects with D-glucose was 12,020 kJ, with 65% of energy from carbohydrate, 15% from protein, 24% from fat, and 38 g of total dietary fiber. The mean test day food intake with L-rhamnose was 11,800 kJ, with 63% of energy from carbohydrate, 16% from protein, 24% from fat, and 61 g of total dietary fiber. The mean test day food intake with lactulose was 11,810 kJ, with 63% of energy from carbohydrate, 16% from protein, 24% from fat, and 62 g of total dietary fiber. Compared with the estimated TEE, the subjects reported consuming ~7% less energy on test days. This difference was not significant.

    Blood samples for fasting lipid concentrations. Serum was collected as previously described and stored at –70°C until analysis (12). Fasting serum lipids were determined, according to the Lipid Research Clinics protocol (21) at the J. Alick Little Lipid Laboratory, St. Michael's Hospital, Toronto, ON, Canada. This laboratory is certified by the Centers for Disease Control/National Heart, Lung, and Blood Institute Lipid Standardization Program. The Technicon RA 1000 analyzer and Technicon reagents were used to measure total cholesterol (Technicon method SM4–0139G86, intra-assay CV, 0.57%) and TG (Technicon method SM4–0173G90, intra-assay CV, 1.85%) (Technicon-Miles). HDL-cholesterol was determined after precipitation of lower-density lipoproteins with dextran sulfate-magnesium chloride (intra-assay CV, 1.47%) (22). LDL-cholesterol was calculated using the formula of Friedewald et al. (23). Serum apolipoproteins (apo) A-1 and B-100 were measured by nephelometry (intra-assay CV, 2.2 and 1.9%, respectively), using Dade-Behring reagents and the Behring BN100 (Dade-Behring). Postprandial free fatty acids were determined by enzymatic analysis (NEF C, ACS-ACOD method, intra-assay CV, 1.9%) (WAKO Chemicals USA).

    Measurements of TGFA and cholesterol biosynthesis. On d 28 of each trial, subjects were given 1.2 g/kg body water (estimated as 60% of total body weight) of deuterium oxide [2H2O, 97.09 atom % excess, Ontario Power Generation (Isotopes Group)] at 0 h, for analysis of fractional synthetic rate (FSR) of cholesterol and TGFA. All beverages were deuterium-enriched (2.4 g 2H2O/L) over the 24-h period following the initial deuterium dose to maintain body water enrichment at plateau and compensate for unlabeled water contained in the solid foods consumed. Plasma samples obtained before and after 24 h of oral administration of 2H2O were used to measure deuterium enrichment in TG and cholesterol fractions as previously described (24,25). Deuterium enrichment of the hydrogen was analyzed using a dual inlet isotope ratio MS (VG Isomass, 903D) with an internal analytical error of 0.17 parts per thousand. The MS was calibrated daily using standard mean ocean water and Greenland ice sheet precipitation as reference standards. Rates of fractional and absolute synthesis of cholesterol and TGFA were determined as previously described (24,26).

    Plasma insulin and glucose. Plasma insulin was analyzed by electrochemiluminescence immunoassay (intra-assay CV <5%) (27) and glucose by an enzymatic reference method with hexokinase (intra-assay CV <3%) (28).

    Serum SCFA. Serum SCFA were measured in 11 subjects as part of another study protocol (12). The SCFA were analyzed by direct on-column injection into a GC system, following vacuum distillation, using previously published methods (11).

    Statistics. All quantitative variables were assessed for normality using the SAS univariate procedure and a logarithmic transformation was applied to the fractional and net synthetic rates for plasma TGFA before conducting further statistical analyses. Repeated-measures ANOVA was conducted using the SAS procedure for mixed models, with a general (unstructured) covariance matrix. To correct for small sample considerations, the df were adjusted by the method of Kenward and Roger (29). The SAS procedure for general linear models, fitting a fixed effects model, was used as a confirmatory analysis. The percentage change values were corrected for baseline using analysis of covariance for a crossover design (30,31).

Repeated-measures ANOVA was also performed on the fractional and net synthetic rates for plasma cholesterol and TGFA (log-transformed), and the summary measures for the 12-h glucose, insulin, TG, FFA, and glycerol data. BMI and age were tested as covariates in the analysis of the 12-h outcomes and the synthetic rate outcomes.

For the correlation analyses, a partial residual regression plot was used to identify influential data points. Pearson correlation coefficients were calculated for the complete data, and recalculated with the outliers removed. Spearman's rank correlations were used to corroborate the parametric analyses. All statistical procedures were performed using version 8.1 of SAS (SAS Institute). Results are expressed as mean ± SEM. Unless otherwise indicated, differences between means were considered significant at P < 0.05.

The physical activity questionnaires were scored in arbitrary units, with strenuous, moderate, and light activities represented by scores of 9, 5, and 3, respectively. Total scores were calculated and analyzed using Friedman's ANOVA by ranks.

Analysis of the lipids from fasting subjects included the subject that missed the lactulose trial. However, TGFA and cholesterol synthesis were not measured for this individual.


   Results
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 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
All subjects tolerated 25 g/d lactulose and D-glucose, but 3 subjects experienced watery stools within 24 h of starting 25 g/d of L-rhamnose. Their dose of L-rhamnose was decreased to 15 g/d for the duration of that study period. There were no significant differences between study periods in self-reported physical activity, as assessed by the physical activity questionnaire.

Sugar type did not affect fasting serum concentrations of total, LDL, or HDL cholesterol, TG, or apoA-1 and B-100, measured either on d 0 or 28 (Table 2). When expressed as a percentage change from baseline, L-rhamnose and lactulose both lowered serum TG, compared with D-glucose, which increased serum TG (P < 0.025, Table 2). There were no significant effects on the percentage changes for the other fasting lipids.


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  		TABLE 2 Fasting serum lipid concentrations in men who ingested 25 g of L-rhamnose, lactulose, or D-glucose and the percentage change over the 4 wk of each treatment period12

 
There were no treatment effects on postprandial plasma TG, FFA, glycerol, glucose, or insulin concentrations in the 11 subjects that participated in the 12-h metabolic test days (Table 3).


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  		TABLE 3 AUC and peak rise for plasma glucose, insulin, TG, FFA, and glycerol in men who ingested 25 g of L-rhamnose, lactulose, or D-glucose over 12 h12

 
Neither the FSR nor the absolute synthetic rate (ASR) for cholesterol was affected by treatment, but analysis of log-transformed values of both the FSR and ASR for TGFA showed that both rates were significantly lower with L-rhamnose and lactulose than with D-glucose (P < 0.01, Table 4).


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  		TABLE 4 Cholesterol and TGFA synthesis rates and amounts synthesized over 24 h in men, after ingesting 25 g/d of L-rhamnose, lactulose, or D-glucose for 4 wk1–2

 
In the 11 subjects that participated in the 12-h metabolic test days, the ratio of acetate to propionate in serum, based on the mean 0–12 h concentration, was higher (P < 0.0005) with lactulose (26 ± 2) than with D-glucose (19 ± 1) or L-rhamnose (18 ± 1). These SCFA results were reported elsewhere (12), and are presented here to facilitate interpretation of the correlation results.

Removal of outliers did not alter the significance of the results; thus, all correlation results are reported for the whole data set, including outliers (see Table 5). The percentage change in TG was positively correlated with the FSR and the ASR of TGFA for all treatments (Table 5). However, within-treatment correlations were significant only for the L-rhamnose data (Table 5 and Fig. 1A). The mean 12-h serum acetate:propionate ratio was negatively correlated with the FSR and the ASR of TGFA for all of the 11 subjects for whom data were available (Table 5). However, within-treatment correlations were significant only for the lactulose data (Table 5 and Fig. 1B).


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  		TABLE 5 Pearson correlations between TGFA synthetic rates in men, and the percentage change in TG and ratio of AC:PR in serum after ingesting 25 g/d of L-rhamnose, lactulose, or D-glucose for 4 wk12

 

Figure 1
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  		Figure 1  Correlations between FSR of TGFA and (A) the percentage change in serum TG concentration in 17 men who ingested L-rhamnose, and (B) the ratio of acetate (AC) to propionate (PR) in serum in 11 men who ingested lactulose, for 28 d. The percentage change was measured over 28 d, and synthetic rates were measured over 24 h on d 28. Points represent values for individual subjects. Regression lines are shown for analyses that included all data points. Pearson's correlation coefficients, based on analysis of all data points, are shown.

 
Of the 11 subjects that participated in the 12-h metabolic test days, 10 were able to tolerate 25 g/d of the unabsorbable sugars. However, side effects were noted by 7 of these subjects. The remaining 3 subjects reported no noticeable side effects with any of the treatments. Consumption of 25 g/d of the unabsorbable sugars was associated with increased flatulence, as previously reported (12). Although lactulose caused moderate flatulence throughout the 4 wk, flatulence with L-rhamnose decreased over this time period, suggesting that at 25 g/d, L-rhamnose was better tolerated. One subject experienced watery stools within 24 h of consuming L-rhamnose (as mentioned above) but when his dose was reduced to 15 g/d, no further side effects occurred.


   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
The results of this study showed that lactulose did not increase serum cholesterol, and L-rhamnose did not lower serum cholesterol, even though L-rhamnose increased serum propionate and lactulose increased the ratio of acetate to propionate in serum, as expected (12). However, both unabsorbable sugars significantly reduced serum TG (expressed as a percentage change) and TGFA synthesis, compared with D-glucose, which had the opposite effects on serum TG and TGFA synthesis. This is of interest because elevated TG is an independent risk factor for cardiovascular disease (32).

These results contradict those of previous studies in which rectal acetate infusion increased plasma total and LDL cholesterol, the addition of propionate to acetate attenuated these effects, and propionate alone had no significant effect on blood lipids (33). However, the results of a 4-wk feeding study may not be expected to agree with those of an acute infusion study in which the amounts of SCFA infused were equivalent to an entire day's colonic production, and plasma metabolites were measured only over 2 h. Most SCFA absorption after rectal infusion likely occurred distally (34), whereas SCFA produced from unabsorbed dietary carbohydrates would be absorbed in the proximal large intestine.

The results of our 4-wk study also differ from those of a 2-wk study in which 20 g/d oral lactulose increased cholesterol in fasting subjects (13). This could be due to an adaptation of response over the last 2 wk. Cecal bacteria in humans can become more efficient at digesting lactulose (35) over periods as short as 1–2 wk, due to increased numbers and activity of bifidobacteria (36). Furthermore, the background diet may influence whether colonic acetate is oxidized or used for lipogenesis. The diets fed in the 2-wk study were relatively high in saturated fat and may therefore have favored lipogenesis (37). Finally, the present study compared the effect of lactulose with that of D-glucose, whereas the comparison in the other study was made against no added sugar (13).

An a priori power analysis, based on an expected 8% difference in total cholesterol between treatments (13), and a pooled SD of 10 for the percentage change in total cholesterol (38–40), suggested that 10 subjects would be sufficient to achieve an {alpha} = 0.05 and ß = 0.2. However, a post hoc power analysis of the present data, with a SD of 18.9, revealed that to detect a significant difference of 10% in total cholesterol between treatments, 25 subjects would have been required. Therefore, given the present data, this study may have lacked sufficient power to detect the expected difference in serum cholesterol concentrations.

Our finding that lactulose caused a negative percentage change in serum TG compared with the effect of D-glucose, differs from the study in which 20 g/d lactulose for 2 wk raised plasma TG, compared with a diet with no added sugar (13). However, in that study, TG actually fell with the consumption of both diets, but to a lesser extent when lactulose was consumed. In the present study, serum TG also tended to fall when lactulose was consumed. The difference between the studies is that our control diet tended to raise serum TG levels. Because our control diet was the D-glucose trial, it included an additional 25 g/d of D-glucose, raising the overall carbohydrate content of the diet, a factor that raises serum TG (41).

A TG-lowering effect of fermentable substrates is consistent with the results of several studies in animals and humans. Psyllium, oat gum, oat bran, and soy fibers were all shown to decrease serum TG by ~10% in rats fed purified diets containing ~67% carbohydrate (42). Supplementing the rat diet with 10% oligofructose decreased the activity of a number of lipogenic enzymes (43), including fatty acid synthase. In humans, the fructooligosaccharide inulin may reduce hepatic lipogenesis and plasma TG, with no changes in plasma cholesterol or cholesterol synthesis (44,45). However, not all studies of inulin show consistent TG-lowering effects in humans. The background diet may need to be relatively high in carbohydrate to demonstrate the TG-lowering effect (44). The background diet in the present study was moderately high in carbohydrate.

Although the mean percentage change in TG was negative for both lactulose and L-rhamnose, 6 subjects taking lactulose and 7 taking L-rhamnose showed a positive percentage change in TG. This may reflect variations in the subjects' background diets, a lack of compliance, or individual differences in responsiveness to the test sugars. Correlation analyses of various dietary components with the primary outcome variables did not suggest that differences in background diet caused the main effects observed, and compliance was excellent. On the other hand, the very fact that subjects in this study had varying blood lipid responses to the same unabsorbed sugars may suggest a role for colonic fermentation in these effects. Other studies showed interindividual differences in microbial fermentation of substrates in the human colon. For instance, the completeness of starch fermentation was shown to range widely among individuals (46). As hypothesized in that study, individual differences in the number and metabolic activity of the colonic bacteria that determine a direct outcome, such as SCFA production, may have an independent effect on the blood lipid profile.

If inhibition of de novo lipogenesis is the primary mechanism for the TG-lowering effect of dietary substrates, only modest effects would be expected because, in humans, de novo lipogenesis is extremely low or variable (47,48) depending on background dietary conditions (44). The direct correlation between the percentage change in fasting TG and rates of TGFA synthesis, together with lower rates of TGFA synthesis when L-rhamnose and lactulose were consumed, in comparison to D-glucose, lend support for this mechanism. The inverse correlation between the ratio of acetate to propionate in serum and the FSR for TGFA on the lactulose treatment suggests that counter to our hypothesis, acetate may actually inhibit TGFA synthesis. However, the same correlation did not occur for the L-rhamnose treatment, in spite of its similar effect on the FSR of TGFA. Because peripheral SCFA concentrations are an indirect measure of their colonic production, a more direct measure of in vivo SCFA production may be needed to test this hypothesis. Therefore, we cannot rule out other aspects of the in vivo metabolism of these sugars as putative agents for the inhibition of TGFA synthesis.

The hypertriacylglycerolemic effect of carbohydrate is typically observed with high-carbohydrate diets (65–75% energy), usually containing mainly simple sugars (49). Carbohydrate intake during wk 4 of each trial was reported to be ~52–55% energy, and measured intake was ~65% on test days. Substituting D-glucose for the other 2 sugars resulted in an extra ~210 kJ/d. Glucose induces lipogenic enzymes, an effect potentiated by insulin (50). However, the present data do not support a role for insulin, and a study showing a direct association between increased plasma TG and fatty acid synthesis with consumption of a 75% carbohydrate diet also did not show a relation with insulin levels (51). The hypertriacylglycerolemic effect of high-carbohydrate diets could be due to decreased clearance of VLDL-TG, rather than increased de novo lipogenesis (52), but clearance was not measured in the present study. Studies in both animals (53,54) and humans (49) showed that fatty acid synthesis can be decreased by substituting a complex carbohydrate for a simple sugar. Our results suggest that substitution with a nondigestible simple sugar has the same effect.

In conclusion, this study showed that neither L-rhamnose nor lactulose affected serum cholesterol, and therefore does not support a primary role for propionate in the cholesterol-lowering effect of soluble fiber. However, the addition of 25 g lactulose or L-rhamnose to the daily diet of healthy men for 4 wk resulted in a negative percentage change in serum TG concentrations. This change was significantly different from the effect of D-glucose, which caused a positive percentage change in serum TG. Consumption of either of the unabsorbable sugars also resulted in significantly lower rates of TGFA synthesis than those seen when D-glucose was consumed. Although the inverse correlation between the ratio of acetate to propionate in serum and the FSR for TGFA when lactulose was consumed is consistent with an inhibitory effect of acetate on TG synthesis, the present data suggest that this cannot be the sole mechanism for the effect of these sugars.


   FOOTNOTES
 
1 Supported in part by the Heart and Stroke Foundation of Canada, and the Natural Sciences and Engineering Research Council. Ontario Power Generation donated a portion of the deuterated water. J.A.V. was supported by a joint Heart and Stroke/Medical Research Council doctoral research award. Back

2 Supplemental Table 1 is available with the online posting of this paper at jn.nutrition.org. Back

7 Abbreviations used: apo, apolipoprotein; ASR, absolute synthetic rate; FSR, fractional synthetic rate; 2H2O, deuterium oxide; SCFA, short-chain fatty acids; TEE, total energy expenditure; TG, triacylglycerol; TGFA, triacylglycerol-fatty acid. Back

Manuscript received 18 January 2006. Initial review completed 2 February 2006. Revision accepted 19 May 2006.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 

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