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Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269
2To whom correspondence should be addressed. E-mail: maria-luz.fernandez{at}uconn.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • HMG-CoA reductase • LDL cholesterol • LDL receptor • lipoprotein lipase • psyllium • triglycerides
The hypocholesterolemic effect of psyllium (PSY)3 as a source of dietary soluble fiber has been widely documented in both human (1
–8
) and animal (9
–15
) studies. Previous results from the subjects whose monocytes were evaluated in the current study demonstrated that PSY intake reduced LDL cholesterol (LDL-C) concentrations in men and premenopausal and postmenopausal women by 8% (7
).
The secondary mechanisms by which PSY lowers plasma cholesterol have been extensively studied in animal models. These mechanisms include a reduction in IDL and LDL-C (11
) associated with decreased apolipoprotein (apo) B containing lipoprotein production (12
) and increased LDL fractional catabolic rate (15
). Furthermore, guinea pigs fed PSY have lower plasma lecithin:cholesterol acyl transferase and cholesteryl ester transfer protein activities than control guinea pigs, which may be associated with compositional modifications of the lipoproteins (16
). Roy et al. (17
) have reported higher activities of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7-
hydroxylase (CYP7A) in guinea pigs fed a PSY-containing diet, suggesting that PSY increased bile acid synthesis, depleting hepatic cholesterol pools and stimulating the up-regulation of HMG-CoA reductase.
The mechanisms by which PSY lowers plasma cholesterol in humans have not been studied in detail. Our data suggested that the hypocholesterolemic effect of PSY is associated with modifications in the intravascular processing of lipoproteins, as indicated by a decrease in cholesteryl ester transfer protein activity (7
) and modifications in the phospholipid content in the LDL particles (18
). Interestingly, we also observed that the effects of PSY on triglyceride (TG) metabolism are modulated by sex and hormonal status. Men experienced a 17% decrease in plasma TG with PSY intake (7
), associated with decreases in plasma concentrations of plasma apoC-III (11%) and apoE (13%), apolipoproteins involved in the regulation of lipoprotein lipase (LPL) activity (18
). In contrast, postmenopausal women had opposite responses in these variables (16% increase in plasma TG, 12% increase in apoC-III and 9% increase in apoE concentrations), whereas premenopausal women experienced no changes in plasma TG or apolipoproteins after PSY intake. Before our study, the effects of PSY on plasma lipids had not been compared among men and premenopausal and postmenopausal women. Thus the interactive effect of sex/hormonal status and PSY on TG metabolism had not been reported.
The aim of the present study was to further explore the mechanisms by which sex and hormone status modulate the effects of PSY on plasma lipids. This objective was accomplished by evaluating HMG-CoA reductase, and LDL receptor and LPL mRNA abundance in mononuclear cells isolated from the same cohort of subjects whose plasma lipids have been previously reported (7
,18
).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Powdered psyllium husks were purchased from Frutarom Meer Corporation (North Bergen, NJ). EDTA, Hanks’ balanced salt solution (HBSS) and Histopaque 1077 were obtained from Sigma Chemical Co. (St. Louis, MO). TriZOL reagent, 1 kb plus DNA ladder, and agarose were obtained from GIBCO BRL (Rockville, MD). A One-Step Reverse Transcription Polymerase Chain Reaction (RT-PCR) kit was purchased from Qiagen (Valencia, CA).
Subjects.
For our clinical intervention, 68 healthy volunteers (24 men, 23 premenopausal women and 21 postmenopausal women free from diabetes, cardiovascular disease or lipid-lowering drug treatment) were recruited and completed the study. Participants were randomly assigned to receive a fiber supplement (15 g of PSY/d) or a placebo (0 g of PSY/d), both provided as cookies, in a crossover design. Participants consumed 100 g of cookies/d, for a period of 30 d, followed by a 21-d washout period. Participants followed the National Cholesterol Education Program step I diet (19
) during both treatment periods. Dietary compliance was assessed by the completion of 7-d dietary records and by recording the returned uneaten portion of cookies. Written informed consent was obtained from each subject, and the study protocol was approved by the Committee on the Use of Human Subjects in Research of the University of Connecticut. The composition of the dietary supplement, baseline characteristics of participants, compliance and diet evaluation during treatment periods have been reported (7
). The present report includes data from a representative subsample of individuals from whom mononuclear cells were available.
Sample collection and mononuclear cell isolation.
At the end of each treatment period, a blood sample was collected into an EDTA-containing tube. Mononuclear cells were isolated from whole blood through centrifugation on a Ficoll gradient according to the method of Boyum (20
). Briefly, 20 mL of blood was diluted with 10 mL of HBSS without Ca2+ and Mg2+, layered over 10 mL of Histopaque 1077 and centrifuged at 500 x g for 30 min. The mononuclear cell interface was removed, washed with HBSS and centrifuged at 600 x g for 10 min twice. The cell pellet was resuspended in 200 µL of Tris buffer (10 mmol of Tris, 150 mmol of NaCl and 1 mmol of CaCl2 per L, pH 7.4) and kept at –70°C until RNA was extracted.
RNA extraction.
Total RNA was extracted from mononuclear cells according to a method based on that developed by Chomczynski and Sacchi (21
). TriZOL reagent was used according to the manufacturer’s instructions; the method was slightly modified by using isopropyl alcohol for RNA precipitation. RNA concentration was estimated by measuring UV light absorbance at 260 nm.
RNA quantification.
HMG-CoA reductase, LDL receptor and LPL mRNA abundance was determined from representative samples using a semiquantitative RT-PCR method adapted from that of Powell and Kroon (22
). Oligonucleotide primers used for amplification were those used by Wang et al. (23
), as follows: for HMG-CoA reductase 5' primer, 5'-TACCATGTCAGGGGTACGTC-3', and 3' primer, 5'-CAAGCCTAGAGACATAATCATC-3' (24
); for LDL receptor 5' primer ,5'-CAATGTCTCACCAAGCTCTG-3' and, 3' primer, 5'-TCTGTCTCGAGGGGTAGCTG-3' (25
); for LPL 5' primer, 5'-GAGATTTCTCTGTATGGCACC-3', and 3' primer, 5'-CTGCAAATGAGACACTTTCTC-3' (26
); and for GAPDH 5' primer, 5'-CATGCCAGTGAGCTTCCCGTT-3', and 3' primer, 5'-GTGGAGTCTACTGGCGTCTTC-3' (27
). The size of reaction products is as follows: for HMG-CoA reductase, 247 bp; for LDL receptor, 258 bp; for LPL, 276 bp; and for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 408 bp. GAPDH was used as an internal control in all reactions. RT-PCR was carried out in a GeneAmp PCR System 9700 (Applied Biosystems, CA) thermal cycler using the Qiagen One-Step RT-PCR kit. The reaction mixture contained 100 ng of total cellular RNA. Amplification was carried out at an annealing temperature of 56°C for 30 cycles for HMG-CoA reductase, 60°C for 30 cycles for the LDL receptor and 56°C for 35 cycles for LPL. Then, 10 µL of each reaction mixture was size fractionated via electrophoresis in a 10 g of agarose/L gel, in 1x Tris-borate/EDTA buffer, and bands were visualized by staining with ethidium bromide. Products were quantified by measuring the relative band intensity using a Nucleovision documentation system with Gel Expert 3.0 software (NucleoTech Corp., San Mateo, CA). Band intensities were corrected based on the GAPDH signal, coamplified in the same reaction.
Statistical analysis.
Paired t tests were used to detect differences in mRNA abundance between fiber and control treatments. Data are presented as means ± SD for the number of subjects in each group. Differences with P < 0.05 were considered significant. Statistical analyses were conducted using SPSS for windows 10.0 (SPSS Inc., Chicago, IL).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, Fig. 1A
). In contrast, HMG-CoA reductase mRNA abundance was increased by PSY (Fig. 1
B): 8, 27 and 25% in men and premenopausal and postmenopausal women, respectively (P < 0.05, Table 1
).
|
|
, Fig. 1c
). LPL mRNA abundance was not affected by PSY in premenopausal women. |
DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Animal studies have shown that PSY intake enhances bile acid excretion (13
), which results in the up-regulation of CYP7A (17
), leading to the depletion of hepatic free cholesterol (9
). In addition, cholesterol absorption may be reduced in the intestinal lumen, resulting in less delivery of cholesterol to the liver by the chylomicron remnants (16
), contributing to the decreased hepatic cholesterol pool (9
). This lowering of hepatic free cholesterol in guinea pigs fed PSY results in an up-regulation of hepatic HMG-CoA reductase activity to compensate for decreased substrate availability (17
). The up-regulation of HMG-CoA reductase or increased hepatic cholesterol synthesis in response to a depletion of hepatic cholesterol has been documented in other animal species fed PSY. PSY intake has been shown to increase rates of hepatic cholesterol synthesis in hamsters (28
). In rats, PSY intake induces significant decreases in hepatic cholesterol, which results in enhanced CYP7A activity and increased CYP7A and HMG-CoA reductase mRNA (29
). In agreement with these studies in animals, PSY intake increased HMG-CoA reductase mRNA abundance in human mononuclear cells in the present study.
One of the major routes for cholesterol removal from the circulation is through receptor-mediated uptake of LDL (30
), which occurs primarily in the liver (31
). Studies in guinea pigs have shown that the hypocholesterolemic effect of dietary fiber, particularly PSY and guar gum, is related to the up-regulation of hepatic LDL receptors (10
,16
). Despite the observed decreases in LDL-C concentrations (7
) induced by PSY in the subjects in the current study, LDL receptor mRNA abundance in monocytes was not affected by PSY intake as would be predicted from previous observations in animals. However, animal studies measured the direct effects of fiber on the LDL receptor in the liver, not in mononuclear cells.
The association between rate of synthesis and mRNA abundance of the LDL receptor has been documented (32
). However, LDL receptor-binding activity varies in different tissues (31
), suggesting that this differential binding activity could account for the lack of increase in LDL receptor mRNA in mononuclear cells. Expression of the LDL receptor and regulation of the expression of this gene have been reported to be tissue specific (33
,34
). Moreover, the different LDL receptor-binding activities among tissues suggests differential regulation of expression of the LDL receptor gene (31
). Powell and Kroon (35
) have documented that LDL receptor gene expression in human mononuclear cells parallels gene expression in the liver in patients who underwent cholecystecomy for gallstones. However, in our present study, PSY intake did not up-regulate the LDL receptor as expected. Because the major impact of the interruption of the enterohepatic circulation of bile acids directly affected the liver, the response observed in the mononuclear cells may more accurately reflect changes that occur in the intravascular compartment.
Similar to our findings, Vidon et al. (36
) have reported that subjects who consumed a high carbohydrate diet had a reduction in total and LDL-C and increased concentrations of HMG-CoA reductase mRNA in mononuclear cells but no changes in LDL receptor gene expression. Interestingly, fiber and fat intakes of these subjects were comparable to those of our participants during the PSY period. By contrast, Plat and Mensink (37
) have documented that the reduction in LDL-C concentrations by plant stanol esters is accompanied by an increase in mononuclear cell LDL receptor mRNA abundance, with no changes in HMG-CoA reductase mRNA.
Sterols regulate expression of both LDL receptor and HMG-CoA reductase genes at the transcriptional level through interaction with sterol response element binding proteins and sterol response elements (38
,39
). However, these two genes are regulated differently at the translational and posttranslational levels (32
,38
). For example, Tam et al. (32
) have reported that the posttranscriptional regulation of the LDL receptor in hepatoma cells and fibroblasts differ in response to decreased circulating levels of lipoproteins.
Effects of PSY on LPL mRNA abundance: interaction with sex and hormonal status.
Both apoC-III and apoE play an important role in the regulation of LPL activity (40
–42
), influencing plasma TG concentrations. ApoC-III, a major component of VLDL, inhibits TG hydrolysis by LPL (43
). Jong et al. (44
) have reported that mice lacking apoC-III hydrolyze TG more efficiently, indicating the inhibitory action of apoC-III on LPL. LPL-mediated TG hydrolysis is also inhibited by apoE, probably by interfering with the binding of apoC-II, an LPL activator (40
,41
). ApoE overexpression contributes to hypertriglyceridemia not only because it promotes VLDL production but also because it impairs VLDL hydrolysis (41
). The hypertriglyceridemic response to PSY in postmenopausal women (7
) occurs in parallel with an increase in plasma apoC-III and apoE concentrations (18
). In contrast, PSY decreased the concentration of these two apolipoproteins, together with a reduction in plasma TG in men. Therefore, the effects of PSY on plasma TG could be in part attributed to the influence of sex and hormonal status on LPL activity, as suggested by changes in the concentration of the LPL inhibitory proteins, apoC-III and apoE.
Consistent with the observed changes in plasma TG after PSY supplementation, LPL mRNA in mononuclear cells was increased in men and decreased in postmenopausal women. These results suggested that the effects of PSY on LPL gene expression are also influenced by sex and hormonal status. Thus, the differences in plasma TG between men and postmenopausal women after PSY supplementation may be explained by a combination of effects, at the level of both LPL gene expression and LPL activity, with the latter mediated by apoC-III and apoE concentrations in plasma.
From this study we concluded that the hypocholesterolemic effect of PSY encompasses modifications in the intravascular processing of the lipoproteins (7
,18
), which lead to changes in the expression of HMG-CoA reductase, an important regulatory enzyme involved in cholesterol homeostasis. In addition, our results suggested that sex and hormonal status influence the effects of PSY on TG metabolism by altering LPL gene expression. Additional research is needed to further explore the effects of PSY on the expression of the LDL receptor in different tissues to better understand how dietary fiber affects this major regulator of plasma LDL-C concentrations.
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; CYP7A, cholesterol 7- hydroxylase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HBSS, Hanks’ balanced salt solution; HMG-CoA, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; LDL-C, LDL cholesterol; LPL, lipoprotein lipase; PSY, psyllium; RT-PCR, reverse transcription-polymerase chain reaction; TG, triglyceride.
Manuscript received 22 August 2002. Initial review completed 24 September 2002. Revision accepted 9 October 2002.
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