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Pectin (PE), guar gum (CC), and psyllium (PSY) lower plasma low density lipoprotein (LDL) cholesterol concentrations in guinea pigs with different orders of magnitude by inducing defined alterations in hepatic cholesterol homeostasis (Fernandez et al. 1994. Am.J Clin. Nutr. 59: 869-879; 61: 127-134 and 1995.J Lipid Res. 3 6 1128-1138). To further explore specific mechanisms responsible for the differences in plasma and hepatic cholesterol lowering, the effects of these fibers were evaluated on cholesterol absorption, hepatic cholesterol 7a-hydroxylase activity, the rate-limiting enzyme of bile acid synthesis, and in vivo LDL transport to target specific primary and secondary mechanisms accounting for the observed responses. Fibers were fed with physiological (0.04%), low cholesterol (LC), or pharmacological high cholesterol (HC) (0.25%) levels to assess whether cholesterol intake influences plasma LDL lowering mechanisms. Intake of PE, GG, or PSY with LC or HC diets lowered plasma and hepatic cholesterol concentrations (P < 0.001). PE and PSY upregulated 7a-hydroxylase activity %fold with LC and PE by 5-fold with HC diets. In contrast, CG intake had no effect on 7a-hydroxylase activity. Cholesterol absorption was reduced 30% by PE intake while no differences were found between control and PSY groups. CG reduced cholesterol absorption only with HC diets. Intake of PE, GG, or PSY with HC diets resulted in faster plasma LDL fractional catabolic rates (FCR) (P < 0.01) with no effect on LDL apoB flux rates (FR) or pool size, suggesting that fiber reduced LDL cholesterol concentration without decreasing the number of LDL particles. In addition to reducing LDL apoB FR, PE and PSY increased LDL FCR with HC diets while GG effects were limited to lowering LDL apoB FR. 1111 These results indicate that the distinctive reductions in hepatic cholesterol induced by PE, GG, and PSY associated with plasma cholesterol lowering result From different mechanisms specific to each fiber and that the levels of dietary cholesterol contribute to the different metabolic responses.-Fernandez, M. L. Distinct mechanisms of plasma LDL lowering by dietary fiber in the guinea pig: specific effects of pectin, guar gum, and psyllium. J. Lipid Res. 1995.36 2394-2404. Supplementary key words lase cholesterol absorption LDL transport cholesterol 7a-hydroxyEpidemiological studies have shown that dietary fiber is protective against coronary heart disease risk (1). Numerous clinical and animal studies have shown that intake of soluble non-starch polysaccharides lowers plasma LDL cholesterol concentrations, therefore reducing the associated risk to cardiovascular disease (2-1 1). Although some of the mechanisms responsible for the observed hypocholesterolemia have been reported for some animal models ( 5 4 , controversy exists regarding specific actions of fiber in the small intestine that result in lower plasma LDL cholesterol concentrations. Abbey, Triantafdidis, and Topping (7) have found that pectin lowers plasma LDL cholesterol in the rat only in combination with high cholesterol diets, while guar gum effects were not different from the control group fed methylcellulose. Decreases in apoB production rates with no effects on plasma LDL turnover were reported as a plasma LDL lowering mechanism by psyllium in the African green monkey (8). In addition, these authors did not find increases in hepatic HMGCoA reductase activity by psyllium intake (8). In contrast, hamsters have been shown to increase LDL receptor expression by PSY intake with high cholesterol diets ( 5 ) and increases in cholesterol synthesis in the liver and extrahepatic tissues have been reported (6). Many mechanisms have been suggested to explain dietary fiber-mediated effects on the resulting hypoAbbreviations: PE, pectin; GG, guar gum; PSY, psyllium; LDL, low density lipoprotein; LC, low cholesterol; HC, high cholesterot; FCR, fractional catabolic rate; FR, flux rate; RID, radial immunodiffusion. 4394 Journal of Lipid Research Volume 36, 1995 by gest, on S etem er 0, 2017 w w w .j.org D ow nladed fom cholesterolemia including decreases in cholesterol absorption (12), binding to bile acids (4), effects on hormones and other parameters (13), and production of volatile fatty acids (14, 15), although controversy exists regarding this last mechanism (16). Based on the effects of soluble fiber on cholesterol and lipoprotein metabolism in guinea pigs (9-1 1) and other studies (5-7) of the proposed mechanisms, decreases in cholesterol absorption and interruption of bile acid enterohepatic circulation are the most likely candidates to explain plasma LDL lowering. In these studies (5-lo), soluble fiber has been shown to up-regulate hepatic HMG-CoA reductase activity (9-1 1) and increase cholesterol synthesis in hepatic and extrahepatic tissues (6), mechanisms not compatible with increased production of volatile fatty acids (16) which would result in decreased synthesis of cholesterol not increases in both liver and extra-hepatic tissues (6,9-11). Previous studies in guinea pigs have shown that the hypocholesterolemic effects of dietary fiber vary in the order of magnitude depending on the ability of the tested fiber to deplete hepatic cholesterol pools. This plasma cholesterol lowering has been associated to the type of fiber and the amount of dietary cholesterol present whether in physiological or pharmacological concentrations (9-1 1). These studies propose that the plasma LDL lowering is directly related to the depletion of hepatic cholesterol by dietary fiber, that the primary and secondary mechanisms accounting for the lowering of hepatic cholesterol concentrations vary depending on the type of fiber, and also that the amount of dietary cholesterol directly affects the metabolic responses. To test this hypothesis, guinea pigs were fed with one insoluble fiber (cellulose) (control diet) and three soluble fibers, pectin (PE), guar gum (GG), or psyllium (PSY), with two different levels of dietary cholesterol equivalent to an absorbed amount of 0.25and 1.5times the endogenous cholesterol synthesis in guinea pigs (17) to evaluate effects of these fibers on cholesterol absorption, hepatic cholesterol 7a-hydroxylase activity, and LDL transport as possible mechanisms associated with plasma LDL lowering. Guinea pigs were chosen in these and previous investigations based on similarities to humans in their observed response to dietary fiber (9-1 1,18), their lipoprotein profile (9-1 l), the distribution of hepatic cholesterol pools (19), absence of forestomach which complicates studies in other animal models (20), and gender similarities in response to dietary fiber (21,22). EXPERIMENTAL PROCEDURES