Gender and hormonal status affect the regulation of hepatic cholesterol 7α-hydroxylase activity and mRNA abundance by dietary soluble fiber in the guinea pig

Abstract

Dietary soluble fiber (SF) consistently lowers plasma LDL cholesterol (LDL-C) concentrations, however, secondary mechanisms governing this reduction are not completely defined. Moreover, these mechanisms appear to differ with gender. Male, female and ovariectomized (to mimic menopause) guinea pigs were used to assess effects of gender, hormonal status and SF on activity and expression of hepatic cholesterol 7α-hydroxylase (CYP7). Diets were identical except for fiber source (control 10% cellulose, SF 5% psyllium/5% pectin). SF intake resulted in 44% lower plasma total cholesterol, 51% lower plasma LDL-C and 22% lower plasma triacylglycerol (TAG) concentrations. However, ovariectomized guinea pigs fed either the control or SF diets, had the highest plasma LDL-C and TAG levels (P<0.01). SF altered hepatic cholesterol metabolism by effectively reducing hepatic free cholesterol, TAG and microsomal free cholesterol, while activity of CYP7, the rate-limiting enzyme of cholesterol catabolism, was up-regulated. Hepatic CYP7 mRNA abundance paralleled the increase in enzyme activity. Ovariectomized guinea pigs had lowest activity and expression of hepatic CYP7 even after intervention with SF. These results suggest that induction of hepatic CYP7 activity may account, in large part, for the hypocholesterolemic effect of SF. Gender and hormonal status influence metabolic responses to dietary SF with estrogen deprivation leading to the most detrimental lipid profile.

Introduction

Dietary soluble fiber (SF) intake has been inversely related to the risk of developing coronary heart disease [1], [2], [3], [4], [5]. Consumption of dietary SF leads to lowering of plasma LDL cholesterol (LDL-C). The intestinal lumen has been widely accepted as the primary site of action of fiber [6]. One of the major primary mechanisms suggested to explain the fiber-mediated lowering of plasma LDL-C is the interruption of the enterohepatic circulation of bile acids [7], which alters hepatic cholesterol homeostasis. Decreased delivery of cholesterol to the liver by chylomicron remnants and a decrease in the hepatic free cholesterol pool, which is the substrate for bile acid synthesis, leads to reduction in hepatic cholesterol concentrations [8], [9].

The body eliminates excess cholesterol by a major regulatory pathway involving the conversion of hepatic cholesterol to bile acids [10]. Hepatic cholesterol 7α-hydroxylase (CYP7) is the initial and rate-limiting enzyme in the bile acid synthesis pathway. This enzyme is subject to feedback inhibition by bile acids fluxing through the liver in the enterohepatic circulation [11]. Studies in guinea pigs have demonstrated an increase in CYP7 activity following dietary SF intake [8], [12]. Similarly, up-regulation in the activity and expression of hepatic CYP7 has been documented in hamsters after psyllium intake, indicating an important role of fiber in increasing the conversion of cholesterol to bile acids in the liver [13].

Previous studies conducted in our laboratory in the guinea pig have indicated that the mechanisms maintaining hepatic cholesterol homeostasis appear to be different in male and female animals. Female guinea pigs were more susceptible to a high cholesterol challenge diet than males, but the intervention by intake of dietary SF was more effective in lowering plasma LDL cholesterol levels in the case of male guinea pigs [14]. In addition, ovariectomized guinea pigs (mimicking menopause) fed a high saturated fat, low-cholesterol diet had higher plasma total and LDL cholesterol, apo B and triacylglycerol (TAG) concentrations, even after feeding dietary SF, when compared to males or females, indicating that estrogen deprivation leads to a detrimental lipid profile [12]. These results suggest that gender and hormonal status may exert a significant influence on the activity and expression of hepatic CYP7 in conjunction with dietary SF intake.

The present studies were conducted to evaluate the effects of gender, hormonal status and dietary SF on the activity and expression of hepatic CYP7 in the guinea pig.