European Journal of Clinical Nutrition (1997) 51, 607±611 ß 1997 Stockton Press. All rights reserved 0954±3007/97 $12.00 Lathosterol and other non- sterols during treatment of hypercholesterolaemia with beta-glucan-rich oat bran

MIJ Uusitupa1, TA Miettinen2, ES Sarkkinen1, E Ruuskanen1, K Kervinen3 and YA KesaÈniemi3

1Department of Clinical Nutrition, University of Kuopio, 2II Department of Medicine, University of Helsinki, and 3Department of Internal Medicine, and Biocenter Oulu University of Oulu, Finland

Objective and subjects: Dietary ®bre has been suggested to interfere with endogenous cholesterol synthesis in the liver. Therefore the effects of oat bran on the proportions of cholesterol synthesis precursors (, D8- cholestenol, and lathosterol), cholestanol and plant sterols (campesterol and beta-sitosterol) to cholesterol were analysed in serum of 36 hypercholesterolaemic subjects. Design: A randomized study of eight weeks duration where beta-glucan-rich oat bran (n ˆ 20, subjects) or wheat bran (n ˆ 16) was used as a part of a cholesterol lowering diet. Plant sterols and cholesterol synthesis precursors were analysed from frozen samples afterward. Results: In the oat-bran group, but not in the wheat bran group, serum total cholesterol declined transiently. The proportions of plant sterols and cholestanol in serum, which re¯ect cholesterol absorption ef®ciency were unchanged. However, the proportions of squalene appeared to be transiently increased during the study. Subjects with apolipoprotein E 4 allele had higher serum campesterol and sitosterol levels (suggestive of ef®cient cholesterol absorption) than those with homozygous apolipoprotein E 3 allele. Conclusions: Since the cholesterol precursors in serum re¯ecting endogenous cholesterol synthesis remained almost unchanged the reduction in the serum cholesterol level by oat bran treatment can not be ascribed to an inhibition of the endogenous cholesterol synthesis. Sponsorship: Supported by the Council for Health Sciences, Academy of Finland and Alko Ltd, Finland. Descriptors: oat bran; beta-glucan; cholesterol; plant sterols; metabolism; Apo E

Introduction Miettinen et al, 1990; Tilvis & Miettinen, 1986). In our previous study, we found attenuation of hypocholestero- Several studies have shown that soluble dietary ®bres, for laemic in¯uence of beta-glucan-rich oat bran with time example plant gums (Anderson, 1985; Jenkins et al, 1979; (Uusitupa et al, 1992a). This ®nding stimulated us to Miettinen et al, 1989; Miettinen, 1987; Todd et al, 1990; analyse cholesterol synthesis precursors and plant sterols Tuomilehto et al, 1988; Uusitupa et al, 1989) and oat bran during treatment with oat-bran to elucidate the mechanism (Anderson et al, 1984; Davidson et al, 1991; Demark- of action, and to ®nd out whether changes in these variables Wahnefried et al, 1990; DeGroot et al, 1963; Van Horn et could explain an elevation of serum cholesterol during al, 1986; Van Horn et al, 1991; Judd & Truswell, 1981; prolonged use of oat bran (Uusitupa et al, 1992b). Kestin et al, 1990; Kirby et al, 1981) lower serum total and LDL-cholesterol levels. The main soluble ®bre portion of oat bran is beta-glucan (AÊ hman et al, 1987). As to the mechanisms of action of soluble dietary ®bre products, two Subjects and methods main theories have been presented; it has been shown that Forty-six subjects with known elevated serum total choles- certain dietary ®bres promote the excretion of cholesterol terol (5.5±8.5 mmol/l) were originally recruited for the as bile acids in the stool thereby upregulating LDL receptor study (Uusitupa et al, 1992a). At the screening phase activity (KesaÈniemi et al, 1990; Miettinen & Tarpila, 1989; three subjects had serum total cholesterol < 5.5 mmol/l, Turner et al, 1990). According to the other theory, fermen- and were therefore excluded. Two subjects refused to tation of dietary ®bre in colon results in the formation of participate for personal reasons. Three subjects in the short chain fatty acids which may have an inhibitory effect wheat bran group dropped out during the ®rst two weeks on hepatic cholesterol synthesis (Anderson, 1985; Chen due to abdominal symptoms considered not related to W-JL et al, 1984). Cholesterol synthesis precursors in wheat bran. Two subjects in the oat bran group discon- serum re¯ect cholesterol synthesis (FaÈrkkilaÈ et al, 1988; tinued the study, one because of operation of breast tumor FaÈrkkilaÈ & Miettinen, 1990; Kempen et al, 1988; Mietti- and one because of gastrointestinal infection. Thus 36 nen, 1970, 1985a, b; Miettinen et al, 1989, 1990; Vuoristo subjects ®nished the study, 20 in the oat bran group and & Miettinen, 1986), while serum plant sterols and to some 16 in the wheat bran group. There were 10 men and 10 extent cholestanol re¯ect absorption and biliary elimination women in the oat bran group. Their mean age was 50 Æ 6y of sterols (FaÈrkkilaÈ et al, 1988; FaÈrkkilaÈ & Miettinen, 1990; and mean body mass index 26.3 Æ 3.3 kg/m2. The wheat bran group consisted of 10 men and 6 women aged 45 Æ 9 y with the mean body mass index of Correspondence: Dr MIJ Uusitupa, Professor in Clinical Nutrition, 2 Department of Clinical Nutrition, University of Kuopio, PO Box 1627, 26.7 Æ 2.5 kg/m . The body weight and body mass index FIN-70211 Kuopio, Finland. remained stable throughout the study. All had been Received 21 February 1997, revised 5 May 1997; accepted 13 May 1997 screened for secondary causes of hyperlipidaemias, and Lathosterol and other non-cholesterol sterols MIJ Uusitupa et al 608 none had antihyperlipidaemic drugs, thyroid, renal or liver Methods disease, abuse of alcohol or diabetes mellitus. Five subjects Weight was measured in the morning with light clothes by (1 in the oat bran and 4 in the wheat bran group) were an electrical weighing machine. An enzymatic method was treated with beta-blockers (acebutolol, metoprolol, ateno- used to determine cholesterol (RoÈschlau et al, 1974). The lol, sotalol, timolol) and 5 (3 and 2, respectively) with Apo E phenotype was determined from the plasma after diuretics (hydrochlorothiazide, or triamteren) for coronary delipidation by isoelectric focusing and immunoblotting heart disease or hypertension. Altogether four women were technique using commercial antibodies (Menzel & Uter- receiving menopausal hormone therapy (3 in the oat bran man, 1986; Enholm et al, 1986). Serum total levels of and 1 in the wheat bran group). Each patient gave informed cholesterol precursors, squalene, D8-cholestenol, lathosterol consent for the study and the study was approved by the and desmosterol, serum total plant sterols, campesterol and Ethics Committee, University of Kuopio. beta-sitosterol, and cholestanol were quantitated with gas- liquid chromatography (GLC) on a 50 m long SE-30 capillary column as described in detail elsewhere (Mietti- Study design nen, 1985; Miettinen & Koivisto, 1983). In the results the A four week run-in period preceded the study. At the serum levels of squalene and non-cholesterol sterols are beginning of the run-in period, medical histories were given as proportions to cholesterol. This expression seems obtained. Clinical examination included blood pressure, preferable for the precursors at least, because reduction of body weight and height; a 12 h overnight venous blood LDL which transports most of non-cholesterol sterols, could sample was taken. Dietary instructions of the lipid-lowering also reduce precursor levels even in the absence of reduced AHA 1 diet were reinforced by clinical dietitians (The cholesterol synthesis. Thus a reduced precursor/cholesterol Expert Panel, 1988). ratio can be considered to re¯ect diminished synthesis while At baseline (0 weeks) the subjects were randomly an increase of the ratio suggests enhanced synthesis. allocated into the oat bran or wheat bran groups, and the Statistical analyses were performed using the SPSS-X- study was carried out with a double-blind study design, program (SPSS Inc, 1988). Multivariate analysis of vari- except for dietitians who had to know the two groups. The ance (MANOVA) for repeated measures was used to ®nd study lasted eight weeks, and subjects visited the clinical out the differences between the groups and the changes research unit after randomisation at two, four and eight within the groups. The results of baseline, four and eight weeks. At 0, 4 and 8 week visits food records were weeks were included in ®nal analyses. If there were no received, body weight was obtained and a 12 h overnight statistically signi®cant overall changes within the groups or fasting venous blood sample was taken. At every visit, differences between the groups in MANOVA, no further serum total cholesterol, LDL-cholesterol, HDL-cholesterol, analyses were conducted. Due to the small number of triglycerides and cholesterol synthesis precursors, choles- subjects in the subgroups, analyses were carried out with tanol and plant sterols were determined. Wilcoxon's (paired samples) and Mann-Whitney's test (unpaired samples), respectively. Pearson's correlation coef®cients were calculated for some pairs of interest. Bran products The results are given as means Æ s.d. All P-values are two-sided. Both oat bran and wheat bran preparations (supplied by Alko Ltd, Helsinki, Finland) were packed in identical sachets of similar volume (200 ml). During the ®rst two Results weeks each subject increased the daily dose stepwise to the whole sachet or the highest tolerable dose. The total ®bre Six subjects in the oat bran group reduced the daily dose content of added wheat bran was 20.5 g and that of oat bran during the study, and two subjects could not increase the 29.8 g, which included 10.3 g of beta-glucan. dose to the target level. The reduction in serum total The oat bran product enriched with beta-glucan (Alko cholesterol was greater in those who used at least two- Ltd, Helsinki, Finland) consisted of 10.3 g of fat, 23 g of thirds of the planned dose of oat bran than in other subjects starch, 20.9 g of protein and 48.1 g of dietary ®bre totally (Uusitupa et al, 1992a). (16.6 g of beta-glucan) in 100 g of dry material. There were no signi®cant differences between the oat bran and wheat bran groups in energy intake, or in the intake of energy nutrients, dietary ®bre and cholesterol during the study. Wheat bran group had a small but Dietary instructions and food records signi®cant decline in ®bre intake from food (added ®bre Subjects received detailed written instructions at the begin- not included) during the study from 24.4 Æ 5.5 to ning of the run-in period to reinforce the principles of the 19.0 Æ 6.4g (P < 0.001), and a marginal increase in mono- AHA 1 diet (30%, 10:10:10 indicating percents of calories enes and decrease in proteins, but otherwise no signi®cant derived from total fat and saturated:monounsaturated: changes were found in the composition of the diets in either polyunsaturated fat). Detailed instructions concerning the group during the study. Table 1 shows the dietary data at diet have been presented elsewhere (Uusitupa et al, 1992a). eight weeks by group. Detailed data on the diets have been Adherence to dietary instructions was followed during the reported previously (Uusitupa et al, 1992a). The total ®bre study by repeated dietary records. Subjects kept food intake, including the added ®bre was 51g for the oat bran records by household measures for four days during the group and 40g for the wheat bran group, assumed that the run-in period and before visits at four and eight weeks. The whole daily dose of ®bre product was taken. After taking nutrient composition of diets was calculated using the into account the energy of oat bran product used, the total Nutrica nutrient calculation program based on a database energy intake was 7041 KJ, fat intake 33.6%, carbohydrate at the Finnish Social Insurance Institute (Rastas et al, intake 46.9% and that of protein 19.5% in the oat bran 1989). group (NS as compared to the wheat bran group). Lathosterol and other non-cholesterol sterols MIJ Uusitupa et al 609 Table 1 Composition of the diets at eight weeks Table 3 Serum total cholesterol, cholesterol synthesis precursors, cholestanol and plant sterols at the beginning of the study by Apo E Oat bran group Wheat bran group phenotypes (n ˆ 20) (n ˆ 16) Apo E 4/4 or Apo E 3/3 Energy (KJ/d) 6963 Æ 2047 7573 Æ 1647 4/3 (n ˆ 16) (n ˆ 19) Fat (% energy) total 32.8 Æ 4.4 33.9 Æ 5.0 Saturated fatty acids 11.2 Æ 2.1 11.7 Æ 1.9 Serum total cholesterol (mmol/l) 7.55 Æ 0.87* 6.82 Æ 0.62 Monounsaturated fatty acids 11.2 Æ 2.1 11.7 Æ 1.9 Squalenea 40 Æ 16 40 Æ 17 Polyunsaturated fatty acids 7.1 Æ 1.3 7.5 Æ 1.6 Cholestenola 8.4 Æ 4.5 10.3 Æ 5.4 Carbohydrates (% energy) 48.0 Æ 4.8 46.7 Æ 4.9 Lathosterola 140 Æ 46 161 Æ 55 Protein (% energy) 17.6 Æ 2.4 17.7 Æ 3.4 Desmosterola 62 Æ 10** 70 Æ 14 Cholesterol (mg/d) 198 Æ 63 224 Æ 80 Cholestanola 140 Æ 25** 122 Æ 24 Fibrea (g/d) 20.9 Æ 7.6 19.0 Æ 6.4 Campesterola 345 Æ 149* 213 Æ 65 Sitosterola 202 Æ 72*** 136 Æ 39 aAdded ®bre not included. Results are given as means Æ s.d. *P < 0.001; **P < 0.05; ***P ˆ 0.002, between the groups. ammol/102 mol of cholesterol Results are given as means Æ s.d. Table 2 gives the results on serum total cholesterol, cholesterol synthesis precursors, cholestanol and plant sterols at baseline, and at four and eight weeks. In the oat P < 0.05), desmosterol (r ˆ 70.31, NS) or lathosterol bran group serum total cholesterol declined signi®cantly (r ˆ 70.66, P < 0.01) were inverse, whereas positive cor- during the ®rst four weeks due to a decease in LDL- relations were found between the changes in the cholesterol cholesterol level (not shown), but at eight weeks serum synthesis precursors: cholestenol vs desmosterol (r ˆ 0.79, total cholesterol did not differ from the baseline level. In P < 0.001), cholestenol vs lathosterol (r ˆ 0.66, P < 0.01), the wheat bran group no signi®cant changes were observed and desmosterol vs lathosterol (r ˆ 0.35, NS). The respec- in serum lipids. In both groups serum squalene/cholesterol tive changes in squalene values were not related to the ratio was increased at four weeks, but at eight weeks it was other cholesterol synthesis precursors or cholestanol. declined to the initial level. The lathosterol/cholesterol ratio We also analysed the variables according to apolipopro- in the oat bran group was nonsigni®cantly higher at eight tein E phenotypes in the whole group at the baseline (Table weeks than at the baseline, but otherwise the concentrations 3), and in the oat bran group separately during the study. of cholesterol synthesis precursors, cholestanol and plant The proportion of desmosterol but not that of other pre- sterols remained unchanged. cursors was signi®cantly lower in the subjects with apo E 4 Correlations between the changes induced by the oat allele (E 4/4 or 4/3), whereas cholestanol, campesterol and bran during the ®rst four weeks in serum cholesterol and sitosterol were higher in the subjects with apo E 4 allele cholesterol precursors were insigni®cant. The respective than in those with apo E 3/3. correlations of cholestanol with cholestenol (r ˆ 70.60, In subjects with apo E4 allele the lathosterol/cholesterol ratio was 155 Æ 57 and 176 Æ 52 (NS) at baseline and at eight weeks, respectively, while these ®gures were Table 2 Serum total cholesterol, cholesterol synthesis precursors, 163 Æ 52 and 170 Æ 53 in subjects with Apo E 3/3 (NS). cholestanol and plant sterols during the study

Time (wk)

Variable/group 0 4 8 Discussion

Total cholesterol (mmol/l) After capillary columns became available for the measure- Oat bran 7.03 Æ 0.81 6.72 Æ 0.97* 6.89 Æ 0.88 ment of non-cholesterol sterols (Miettinen & Koivisto, Wheat bran 7.27 Æ 0.85 7.40 Æ 0.80 7.30 Æ 0.71 1983), the determinations of demethylated precursors of Squalenea cholesterol in serum have been applied to study the endo- Oat bran 39 Æ 14 64 Æ 19** 38 Æ 13 genous cholesterol synthesis in different clinical situations Wheat bran 42 Æ 20 55 Æ 17*** 37 Æ 17 Cholestenola (FaÈrkkilaÈ & Miettinen, 1990; Kempen et al, 1988; Mietti- Oat bran 10 Æ 5 13 Æ 7 11 Æ 4 nen, 1985; Miettinen & Koivisto, 1983). In the present Wheat bran 8 Æ 5 9 Æ 6 8 Æ 6 study, oat bran was compared with the wheat bran since the Lathosterola latter ®bre has been known to be neutral regarding the Oat bran 160 Æ 51 166 Æ 49 170 Æ 51 Wheat bran 141 Æ 50 133 Æ 63 141 Æ 71 effects on serum cholesterol concentration. There was a Desmosterola temporary increase in the concentration of squalene both in Oat bran 68 Æ 14 67 Æ 14 67 Æ 10 the oat bran and wheat bran groups, even though in the Wheat bran 64 Æ 12 59 Æ 11 63 Æ 13 former studies squalene has not been proven to be an a Cholestanol accurate, long-term measure for endogenous cholesterol Oat bran 128 Æ 27 126 Æ 29 127 Æ 28 Wheat bran 134 Æ 23 132 Æ 24 133 Æ 24 synthesis. From the other precursors of cholesterol, lathos- 8 Campesterola terol and to some extent also D -cholestenol and desmos- Oat bran 250 Æ 122 254 Æ 124 254 Æ 126 terol, have been used for evaluation of the whole body Wheat bran 304 Æ 130 309 Æ 111 327 Æ 136 cholesterol synthesis (FaÈrkkilaÈ et al, 1988; FaÈrkkilaÈ & Sitosterola Oat bran 153 Æ 55 164 Æ 59 158 Æ 58 Miettinen, 1990; Kempen et al, 1988; Miettinen, 1970, Wheat bran 175 Æ 73 185 Æ 67 178 Æ 71 1985; Miettinen et al, 1989, 1990; Miettinen & Vuoristo & Miettinen, 1986). It has been shown that serum lathosterol *P ˆ 0.028. positively correlates with hepatic HMG-CoA reductase **P < 0.001 as compared to the baseline. ***P ˆ 0.034 as compared to the baseline. activity in humans (BjoÈrkheim et al, 1987). Furthermore, ammol/102 mol of cholesterol. the lathosterol/cholesterol ratio decreases by HMG-CoA Results are given as means Æ s.d. reductase inhibitors (Kempen et al, 1988; Vanhanen et al, Lathosterol and other non-cholesterol sterols MIJ Uusitupa et al 610 1992), whereas its level is markedly increased by choles- BjoÈrkheim I, Miettinen T, Reihner E, Ewerth S, Angelin B & Einarsson K tyramine (Gylling et al, 1989) and guar gum, even in the (1987): Correlation between serum levels of some cholesterol precur- sors and activity of HMG CoA reductase in human liver. J. Lipid Res. presence of lovastatin (Uusitupa et al, 1992b). In the 28, 1137±1143. present study, lathosterol/cholesterol ratio did not change Chen W-JL, Anderson JW & Jennings DJA (1984): Propionate may signi®cantly by the oat ban treatment. By contrast, the mediate the hypocholesterolemic effects of certain soluble plant ®bers results obtained by plantago ovata and guar gum prepara- in cholesterol-fed rats. Proc. Soc. Exp. Biol. Med. 175, 215±218. tions (Miettinen & Tarpila, 1989; Uusitupa et al, 1992b) Davidson MH, Dugan LD, Burns JH, Bova J, Story MK & Drennan KB (1991): The hypocholesterolemic effects of beta-glucan in oatmeal and suggest that the endogenous cholesterol synthesis could be oat bran. A dose controlled study. JAMA 265, 1833±1839. increased by some soluble ®bre products. De Groot MR, Luyken R & Pikaar NA (1963): Cholesterol-lowering effect Positive correlations have been reported between cho- of rolled oats. Lancet 2, 303±304. lesterol absorption ef®ciency and serum proportions of Demark-Wahnefried W, Bowering J & Cohen PS (1990): Reduced serum cholesterol with dietary change using fat-modi®ed and oat bran supple- cholestanol, (the 5-a-saturated derivative of cholesterol), mented diets. J. Am. Diet. Assoc. 90, 223±229. campesterol and sitosterol (Miettinen et al, 1989). In the Ehnholm C, Lukka M, Kuusi T, NikkilaÈ E & Utermann G (1986): present study, the levels of these variables remained Apolipoprotein E polymorphism in the Finnish population: gene fre- unchanged. This suggests that the two ®bre products did quencies and relation to lipoprotein concentrations. J. Lipid Res. 27, not interfere with the absorption of cholesterol in a sig- 227±235. FaÈrkkilaÈ M & Miettinen TA (1990): Lipid metabolism in bile acid ni®cant manner, a ®nding proposed for soluble ®bres malabsorption. Ann. Med. 22, 5±13. (Miettinen, 1987; Miettinen & Tarpila, 1989). FaÈrkkilaÈ MA, Tilvis RS & Miettinen TA (1988): Regulation of plasma As in some previous studies (KesaÈniemi et al, 1987; plant sterol levels in patients with gut resections. Scand. J. Clin. Lab. Miettinen & KesaÈniemi, 1988), the cholestanol and plant Invest. 48, 715±722. FaÈrkkilaÈ MA, Tilvis RS & Miettinen TA (1988): Raised plasma cholesterol sterol ratios to cholesterol were higher in subjects with apo precursors in patients with gut resections. Gut 29, 188±195. E 4/4 or 4/3 phenotypes than in those with Apo E 3/3. Gylling H, Vanhanen H & Miettinen TA (1989): Effects of acipimox and Cholesterol synthesis precursors, especially the desmos- cholestyramine on serum lipoproteins, non-cholesterol sterols and terol/cholesterol ratio, were on the other hand decreased cholesterol absorption and elimination. Eur. J. Clin. Pharmacol. 37, in subjects with apo E 4/4 or 4/3, a ®nding re¯ecting a 111±115. Jenkins DJA, Leeds AR, Slavin B, Mann J & Jepson EM (1979): Dietary diminished endogenous cholesterol synthesis in subjects ®ber and blood lipids: reduction of serum cholesterol in type II with apo E 4/4 or 4/3 (KesaÈniemi et al, 1987). Because high hyperlipidemia by guar gum. Am. J. Clin. Nutr. 32, 16±18. plant sterol and cholestanol proportions in serum re¯ect an Judd PA & Truswell AS (1981): The effect of rolled oats on blood lipids ef®cient absorption of dietary cholesterol (Tilvis & Mietti- and fecal excretion in man. Am. J. Clin. Nutr. 34, 2061±2067. Kempen HJM, Glatz JFC, Leuven JAG, van der Voort HA & Katan MB nen, 1986; Miettinen et al, 1989, 1990), the data are (1988): Serum lathosterol concentration is an indicator of whole-body consistent with previous observations which suggest that cholesterol synthesis in humans. J. Lipid Res. 29, 1149±1155. apo E polymorphism may affect the ef®ciency of choles- Kestin M, Moss R, Clifton PM & Nestel PJ (1990): Comparative effects of terol absorption (KesaÈniemi et al, 1987; Miettinen & three cereal brans on plasma lipids, blood pressure, and glucose KesaÈniemi, 1988) and subsequently cholesterol synthesis; metabolism in mildly hypercholesterolemic men. Am. J. Clin. Nutr. 52, 661±666. the higher the absorption the lower the synthesis of endo- KesaÈniemi YA, Ehnholm C & Miettinen TA (1987): Intestinal cholesterol genous cholesterol. Since the ®bres used in this study absorption ef®ciency in man is related to apoprotein E phenotype. obviously had little effect on cholesterol absorption no J. Clin. Invest. 80, 578±581. consistent change was observed even in the subjects with KesaÈniemi YA, Tarpila S & Miettinen TA (1990): Low vs high dietary ®ber and serum, biliary, and fecal lipids in middle-aged men. Am. J. high cholesterol absorption associated with Apo E 4 allele. Clin. Nutr. 51, 1007±1012. A high serum level of cholestanol, the 5-a-saturated Kirby RW, Anderson JW, Sieling B, Rees ED, Chen W-JL, Miller RE & derivative of cholesterol, re¯ects high ef®ciency of intest- Kay RM (1981): Oat bran intake selectively lowers serum low density inal sterol absorption, and is accordingly inversely related lipoprotein cholesterol concentrations of hypercholesterolemic men. to endogenous cholesterol synthesis and fecal excretion of Am. J. Clin. Nutr. 34, 824±829. Menzel H-J & Utermann G (1986): Apolipoprotein E phenotyping from neutral sterols (Miettinen et al, 1989). Although no sig- serum by Western blotting. Electrophoresis 7, 492±495. ni®cant changes were observed in the mean values of Miettinen TA & KesaÈniemi YA. (1988): Cholesterol absorption regulates cholestanol and cholesterol synthesis precursors, the cholesterol metabolism and within-population variation of serum changes in the proportion of cholestanol were inversely cholesterol. In Hyperlipidaemia and Atherosclerosis, eds. KE Suckling & PHE Groot, pp 73±82. New York: Academic Press. correlated with those of the cholesterol precursors in the oat Miettinen TA (1970): Detection of changes in human cholesterol meta- bran group. This ®nding con®rms an inverse relationship bolism. Ann. Clin. Res. 2, 300±320. between the proportion of cholestanol in serum and cho- Miettinen TA (1985a): Precursor sterols related to cholesterol synthesis. In lesterol synthesis, but does not give further information Proceedings of the NATO Meeting, Coordinate Regulation of Choles- regarding the mechanisms behind this ®nding. terol Metabolism, ed. A Sanghvi, pp 87±106. Santa Fe, NM; Pittsburgh, PA: University of Pittsburgh School of Medicine. Miettinen TA (1985b): Cholesterol precursors and their diurnal rhythm in Conclusions lipoproteins of patients with jejuno-ileal bypass and ileal dysfunction. Metabolism 34, 425±430. Cholesterol synthesis precursors in serum remained almost Miettinen TA (1987): Dietary ®ber and lipids. Am. J. Clin. Nutr. 45, 1237± unchanged during both the oat bran and wheat bran treat- 1242. ment. Neither oat bran nor wheat bran affected serum plant Miettinen TA, Tilvis RS & KesaÈniemi YA (1989): Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged sterol levels in this study. men. Metabolism 38, 136±140. Miettinen TA, Tilvis RS & KesaÈniemi YA (1990): Serum plant sterols and References cholesterol precursors re¯ect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am. J. Epidemiol. Anderson JW (1985): Physiological and metabolic effects of dietary ®ber. 131, 20±31. Fed. Proc. 44, 2902±2906. Miettinen TA & Koivisto P (1983): Non-cholesterol sterols and bile acid Anderson JW, Story L, Sieling B, Chen W-JL, Petro MS & Story J (1984): production in hypercholesterolaemic patients with ileal bypass. In Bile Hypocholesterolemic effects of oat-bran or bean intake for hypercho- Acids and Cholesterol in Health and Disease, eds. G Paumgartner, A lesterolemic men. Am. J. Clin. Nutr. 40, 1146±1155. Stiehl & W Gerok, pp 183±187. Lancaster, NY: MTP. Lathosterol and other non-cholesterol sterols MIJ Uusitupa et al 611 Miettinen TA & Tarpila S (1989): Serum lipids and cholesterol metabo- relation to Apolipoprotein E phenotype. J. Am. Coll. Nutr. 11/6, 651± lism during guar gum, plantago ovata and high ®bre treatments. Clin. 659. Chim. Acta. 183, 253±262. Uusitupa MIJ, Miettinen TA, Happonen P, Ebeling T, Turtola H, Vouti- Rastas M, SeppaÈnen R, Knuts L-R, Karvetti R-L & Varo P (eds) (1989): lainen E & PyoÈraÈlaÈ K (1992b): Lathosterol and other noncholesterol Nutrient Composition of Foods. Helsinki, Finland: Publications of the sterols during treatment of hypercholesterolemia with lovastatin alone Social Insurance Institution. and with cholestyramine and guar gum. Arterioscler. Thromb. 12, 807± RoÈschlau P, Bernt E & Gruber W (1974): Enzymatische Bestimmung des 813. Gesamt-Cholesterins im Serum. Z. Klin. Chem. Biochem. 12, 403±407. Uusitupa M, Siitonen O, Savolainen K, Silvasti M, PenttilaÈ I & Parviainen SPSS Inc (1988): SPSS-X User's Guide, 3rd edn, Chicago, USA, pp 569±641. M (1989): Metabolic and nutritional effects of long-term use of guar The Expert Panel (1988): Report of the National Cholesterol Education gum in the treatment of non-insulin-dependent diabetes of poor meta- Program expert panel on detection, evaluation, and treatment of high bolic control. Am. J. Clin. Nutr. 49, 345±351. cholesterol in adults. Arch. Intern. Med. 148, 36±69. Van Horn LV, Liu K, Parker D, Emidy L, Liao Y, Harn Pan W, Giumetti Tilvis R & Miettinen TA (1986): Serum plant sterols and their relation to D, Hewitt J & Stamler J (1986): Serum lipid response to oat product cholesterol absorption. Am. J. Clin. Nutr. 43, 92±97. intake with a fat-modi®ed diet. J. Am. Diet. Assoc. 86, 759±764. Todd PA, Ben®eld P & Goa KL (1990): Guar gum. A review of its Van Horn L, Moag-Stahlberg A, Liu K, Ballew C, Ruth K, Hughes R & pharmacological properties, and use as a dietary adjunct in hypercho- Stamler J (1991): Effects on serum lipids of adding instant oats to usual lesterolemia. Drugs 39, 917±928. American diets. Am. J. Public Health 81, 183±188. Tuomilehto J, Silvasti M, Aro A, Koistinen A, Karttunen P, Gref C-C, Vanhanen H, KesaÈniemi YA & Miettinen TA (1992): Pravastatin lowers Ehnholm C & Uusitupa M (1988): Long term treatment of severe serum cholesterol, cholesterol precursor sterols, fecal and hypercholesterolemia with guar gum. Atherosclerosis 72, 157±162. cholesterol absorption in man. Metabolism 41, 588±595. Turner PR, Tuomilehto J, Happonen P, La Ville AE, Shaikh M & Lewis B Vuoristo M & Miettinen TA (1986): Serum cholesterol precursor sterols in (1990): Metabolic studies on the hypolipidaemic effect of guar gum. coeliac disease: Effects of glutein free diet and cholestyramine. Gut 27, Artherosclerosis 81, 145±150. 1312±1319. Uusitupa MIJ, Ruuskanen E, MaÈkinen E, Laitinen J, Toskala E, Kervinen AÊ hman P & Graham H (1987): Mixed-linked (1-3), (1-4)-D-glucans in the K & KesaÈniemi YA (1992a): A controlled study on the effect of beta- cell walls of barley and oatsÐchemistry and nutrition. Scand. J. glucan-rich oat bran on serum lipids in hypercholesterolemic subjects: Gastroenterol. 22 (Suppl. 129), 42±51.