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2 Centre for Nutrition Modelling, Department of Animal and Poultry Science and Departments of 3 Human Health and Nutritional Science and 4 Food Science, University of Guelph, Guelph, Ontario, Canada N1G 2W1; 5 Food Research Program, Agriculture and Agri-Food Canada, Guelph, Ontario, Canada N1G 5C9; and 6 Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada M5G 2C4
* To whom correspondence should be addressed. E-mail: trideout{at}uoguelph.ca or mfan{at}uoguelph.ca.
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ABSTRACT |
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Introduction |
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The liver plays a major role in regulating systemic cholesterol homeostasis by converting cholesterol into bile and secreting both bile acids and free cholesterol into the gut lumen via the bile duct (4). Furthermore, hepatic lipoprotein receptors, including LDL receptor (LDLr)7 and scavenger receptor class B, type 1 (SR-B1), are the gateways of hepatic cholesterol metabolism (5,6).
Guar gum (GG) is a viscous polysaccharide extracted from the seed of the legume plant Cyamopsis tetragonolobus that has been reported to have hypocholesterolemic effects in guinea pigs (7), rats (8), and humans (9). Previous metabolic studies have greatly enhanced our understanding of how lipoprotein metabolism is modified by soluble fiber consumption (10,11). However, the molecular mechanisms that mediate these diet-induced hypolipidemic effects have mainly been examined at the mRNA level (12,13) with little emphasis on posttranscriptional events that regulate the protein abundance of gene products that direct hepatic cholesterol metabolism. Furthermore, although the importance of sterol regulatory element binding protein 2 (SREBP2) in regulating hepatic cholesterol homeostasis is well documented (14), no information is available concerning the effect of dietary fibers on the transcription and maturation of the nuclear active form of SREBP2.
To develop effective, functional food-based therapies to prevent hypercholesterolemia, a detailed understanding of how dietary fibers modulate specific transcriptional and translational events in the expression of genes that regulate hepatic cholesterol metabolism is paramount. Therefore, the present work was undertaken to examine the hypocholesterolemic effects of GG consumption and gain insight into how GG regulates the mRNA and protein expression of hepatic LDLr, SR-B1, and SREBP2 in pigs fed an atherogenic diet.
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Materials and Methods |
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An atherogenic basal (control) diet was formulated with poultry meal (45%) and casein (4%) as the major protein sources and an exogenous fat blend (15%; Table 1). The experimental diet was similar to the control but was supplemented with 10% GG at the expense of cornstarch. Commercial mineral and vitamin premixes were added to the diets to meet or exceed NRC (15) recommendations.
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Sample collection and processing. Blood samples (10 mL) were collected from the orbital sinus on d 0 (baseline) and d 36 of the experiment following a 12-h food deprivation period. Plasma was separated from whole blood by centrifugation at 1000 x g for 10 min and stored in 2-mL aliquots at –80°C. On d 36 of the experiment, pigs were anesthetized [isoflurane (2.5%) in O2 (2.5 L/min)] and liver samples were collected and processed according to previously published procedures (18).
Chemical analyses. Plasma concentrations of total cholesterol, HDL-cholesterol, and triglyceride were measured by enzymatic colorimetric assays (International Bio-Analytical Industries, part nos. 152, 158, and 452, respectively). LDL-cholesterol was estimated by the difference method using the Friedewald formula (19).
Total and free cholesterol concentrations in diet and liver samples were analyzed directly by spectrophotometric analyses using a cholesterol/cholesterol ester quantification kit (Biovision Research Products). Cholesterol ester concentrations were determined as the difference between total and free cholesterol according to the kit instructions.
Immunoblot analyses. Tissue extracts for immunoblot analyses of LDLr and SR-B1 were prepared, as previously described (20), while SREBP2 analyses were conducted on nuclear and cytoplasmic extracts prepared using CelLytic NuCLEAR Extraction kit (Sigma). Immunoblot analysis was conducted according to previously published procedures (21) with the following antibodies: anti-LDL (Chemicon International), anti-SR-B1 (Novus Biologicals), and anti-SREBP2 (Lab Vision).
Design of oligonucleotide primers. Primers for amplification of target and housekeeping genes were developed using Primer 3 (22) and Spidey (23) software and were designed to overlap at least 2 exon boundaries. Primer sequences were as follows: 1) LDLr [AF067952 (24), estimated product size, 141 bp]: 5'-GGATTTGTGATGG-GAACACC-3' and 5'-CGTCACACCTCAAGACTCA-3'; 2) SR-B1 [NM_213967 (25), estimated product size, 150 bp]: 5'-GACAAACCGGGAAGATTGAA-3' and 5'-GAGCAAGGAGCACGTACTGG-3'; 3) SREBP2 [DQ020476 (26), estimated product size, 151 bp]: 5'-GCTTCTCCCCCTACTCCATC-3' and 5'-GAGAGGCACAG-GAAGGTGAG-3'; and 4) ß-actin [AY550069 (27), estimated product size, 150 bp]: 5'-GGATGCAGAAGGAGATC-ACG-3' and 5'-ATCTGCTGGAAGG-TGGACAG-3'.
RNA preparation and real time RT-PCR.
Total RNA was isolated from whole liver tissue using TRIzol reagent (Invitrogen Canada). RNA concentration and integrity were determined with spectrophotometry (260 nm) and agarose gel electrophoresis, respectively. RNA was treated with DNase (Invitrogen) and quantitative real time RT-PCR was performed in a Smart Cycler (Cepheid) using Quantitect SYBR Green RT-PCR kit (Qiagen) according to kit instructions. Target gene expression was normalized against that of ß-actin and relative gene expression was determined using the 
Ct method (28).
Statistical analyses. Data were analyzed using the PROC MIXED model of SAS. Data are presented as means ± SEM. Differences from the control were considered significant at P < 0.05. Baseline plasma lipid endpoints measured on d 0 were included as a covariate in the statistical analyses of these endpoints collected on d 36.
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Results |
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4.1 and 4.6%, respectively (Table 1). However, daily food intake [839 ± 28 vs. 775 ± 33 g · pig–1 · d–1] and daily gain [653 ± 20 vs. 567 ± 30 g · pig–1 · d–1] did not differ (P = 0.16) between the control and the GG-supplemented groups, respectively. In pigs fed the GG diet, plasma total and LDL-cholesterol concentrations were 27 and 37% lower (P < 0.05), respectively, compared with pigs fed the control diet (Table 2). GG consumption also tended to lower the plasma HDL-cholesterol concentration (P = 0.09) and the LDL-/HDL-cholesterol ratio (P = 0.08). Plasma triglyceride concentrations did not differ (P = 0.80) between pigs fed GG (0.30 ± 0.10 mmol/L) and the control diet (0.25 ± 0.02 mmol/L). Although hepatic total cholesterol (27.18 ± 1.18 vs. 23.73 ± 1.83 µmol/g tissue) and cholesterol ester (26.79 ± 1.18 vs. 23.45 ± 1.82 µmol/g tissue) tended to be lower (P = 0.12–0.13) in the GG group compared with the control group, hepatic free cholesterol (0.38 ± 0.03 vs. 0.28 ± 0.05 µmol/g tissue) was reduced (P < 0.05) in response to GG supplementation.
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Similar to the hypocholesterolemic effects observed in this study, previous investigations with animals (29–31) and humans (32) demonstrated a reduction in plasma cholesterol in response to GG consumption. Whereas plasma HDL-cholesterol tended to be lower in pigs fed GG in this study, previous investigations have highlighted a remarkable variability in the response of plasma HDL-cholesterol to GG consumption (33–35). Generally, dietary strategies that lower plasma LDL-cholesterol often produce a parallel decrease in plasma HDL-cholesterol concentrations (36–38). Although there is concern that the cardio-protection associated with low LDL-cholesterol is diminished with simultaneous reductions in HDL-cholesterol, the physiological implications in this study are most likely minor, as the LDL-/HDL-cholesterol ratio tended to be lower in pigs fed GG.
In response to GG consumption, mRNA and protein expression of the hepatic LDLr were increased. The LDLr is predominantly expressed in the liver and is transcriptionally regulated in a nonsterol and sterol-dependent manner. Nonsterol transcriptional regulation of the LDLr involves transcription factor early growth response 1 in association with the sterol-independent regulatory element (39), estrodiol-stimulated expression through the estrogen response element (40), and insulin-stimulated expression through SREBP1a (41). Sterol-dependent transcription of the LDLr is regulated through SREBP2 (42) and more recently with the liver X receptor (43). Although less is known concerning the posttranslational control of the LDLr, recent work suggests that convertase subtilisin/kexin type 9, a proteinase regulated by SREBP2, enhances the degradation of the LDLr protein (44). Surprisingly, although previous studies have demonstrated increased hepatic LDLr mRNA expression following consumption of psyllium (45), resistant starch (46), and mushroom fiber (47), we are unable to find any reports concerning the effects of GG consumption on hepatic LDLr mRNA and/or protein expression. Although the correlation between LDLr protein abundance and binding activity is unknown, the results of this study suggest that GG consumption lowers plasma cholesterol by enhancing LDL clearance through the hepatic LDLr protein. Accordingly, previous investigations observed enhanced LDL apolipoprotein B turnover and LDL fractional catabolic rate in response to GG consumption (7,30).
The expression of hepatic SR-B1 is regulated by a wide range of physiological stimuli (48–53) and is believed to mediate the selective uptake of cholesterol ester from HDL in the reverse cholesterol transport system (54). The discrepancy between the mRNA and protein expression of SR-B1 in this study supports a posttranscriptional regulation of SR-B1 and confirms previous work suggesting that the transcript level of the human homolog of SR-B1, CD36, and LIMPII analogous-1, does not correlate with protein abundance (55). The reduction in hepatic SR-B1 mRNA without a concomitant change in SR-B1 protein abundance suggests that hepatic HDL clearance through SR-B1 was not affected by GG consumption. In accordance with this hypothesis, Woollett et al. (56) reported that psyllium consumption drastically reduced plasma HDL-cholesterol concentrations but did not alter the absolute flux of HDL-cholesterol ester to the liver in a hamster model. Furthermore, whereas SREBP2 has been shown to up-regulate the expression of murine SR-B1 and its human homolog CD36 and LIMPII analogous-1 (55), our results suggest that the porcine SR-B1 gene transcript is not regulated in an SREBP-dependent manner, as increased nuclear SREBP2 protein was associated with a reduction in hepatic SR-B1 mRNA.
To our knowledge, this is the first report of increased hepatic SREBP2 protein expression in response to dietary fiber consumption. At the transcriptional level, hepatic cholesterol metabolism is tightly controlled through SREBP2, a nuclear receptor that binds to sterol response elements in the promoter region of a multitude of target genes (42). Under normal physiological concentrations of cholesterol, SREBP2 precursor proteins are anchored to the endoplasmic reticulum in close association with sterol cleavage activating protein (SCAP). In response to a cellular requirement for cholesterol, the SREBP-SCAP complex translocates to the Golgi apparatus where the transcriptionally active NH3-terminal domain is released following a 2-step proteolytic cleavage (14). Through a nuclear targeting mechanism involving importin ß (57), the NH3-terminal domain enters the nucleus and upregulates the transcription of target genes, including the LDLr. Previous work suggests that dietary fish oil (58) and soy isoflavones (59) can affect the maturation and proteolytic release of SREBP. The expression of SREBP2 mRNA was not affected by GG feeding in this study. Thus, the parallel increase in the cytoplasmic precursor and nuclear forms of SREBP2 without a corresponding increase in the cytoplasmic mature form suggests that nuclear SREBP2 abundance may have been enhanced by posttranscriptional events independent of the proteolytic cleavage at the Golgi apparatus. Posttranslational polyubiquitination followed by proteosome-mediated degradation has been shown to regulate nuclear SREBP2 protein abundance (60). Although the hypocholesterolemic effects of green tea polyphenols have recently been attributed to an inhibition of proteosome activity and an accumulation of nuclear SREBP2 (61), more research is needed to clarify if GG and similar soluble fibers have any effect on SREBP protein degradation.
Unlike soy isoflavones that have been hypothesized to directly regulate the transcription of hepatic cholesterol-responsive genes (62), dietary fiber components are not absorbed from the gastrointestinal tract and therefore are generally thought to influence plasma and hepatic cholesterol homeostasis through secondary mechanisms (7). Free cholesterol has recently been shown to directly bind to SCAP and induce a conformational change that promotes association with insulin-induced gene 1, an endoplasmic reticulum retention protein that prevents the movement of the SREBP-SCAP complex to the Golgi apparatus (63). Therefore, the results of this study suggest that the reduction in hepatic free cholesterol concentration in response to GG consumption, possibly the result of an interference with intestinal cholesterol or bile acid absorption, may have been the primary signal that mediated the upregulation of the LDLr in response to GG consumption.
In conclusion, GG consumption reduces free cholesterol concentration in the liver and stimulates an accumulation of nuclear SREBP2 through posttranscriptional event(s) independent of the proteolytic release of the mature protein at the Golgi apparatus. Accordingly, SREBP2-dependent upregulation of hepatic LDLr enhances cholesterol clearance by the liver and is at least partially responsible for the hypocholesterolemic effects associated with GG consumption in the pig model.
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FOOTNOTES |
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7 Abbreviations used: DE, digestible energy; GG, guar gum; LDLr, LDL receptor; NE, net energy; SCAP, sterol cleavage activating protein.; SR-B1, scavenger receptor class B, type 1; SREBP2, sterol regulatory element binding protein 2.
Manuscript received 6 November 2006. Initial review completed 21 November 2006. Revision accepted 22 December 2006.
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