Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

Abstract

These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any genderrelated differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 mol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 mol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25.3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2.1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7␣-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 mol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels. (HEPATOLOGY 1998;28:1088-1094.)The central role that the liver plays in the maintenance of whole-body sterol balance and the regulation of plasma low-density lipoprotein (LDL)-cholesterol levels stems partly from its unique ability to convert cholesterol to bile acids, the excretion of which represents a major route for the elimination of cholesterol from the body.

Mice Expressing the Human CYP7A1 Gene in the Mouse CYP7A1 Knock-out Background Lack Induction of CYP7A1 Expression by Cholesterol Feeding and Have Increased Hypercholesterolemia When Fed a High Fat Diet

“…A more likely explanation for the differences between the human and mouse CYP7A1 gene expression, however, is that endogenous sterols, such as 27-OH-cholesterol (31), induce expression of the mouse CYP7A1 gene through the LXR element to a greater degree than hepatocyte nuclear factor-1 stimulates the human gene, thus allowing greater expression of the mouse gene despite the size of its bile acid pool. The differences in the amounts of CYP7A1 mRNA in male and female mice is consistent with previous reports (32,33) concluding that gender-related differences in the bile acid pool size are caused by differences in CYP7A1 expression and not by differences in the alternate pathway of bile acid synthesis, because the effect of gender was not observed in CYP7A1 Ϫ/Ϫ mice (23). In the mCYP7A1 Ϫ/Ϫ /hCYP7A1 mice, there were no differences between male mice and female mice.…”

Expression Cloning of an Oxysterol 7α-Hydroxylase Selective for 24-Hydroxycholesterol

“…1 and 6). Sexually dimorphic expression patterns of the CYP7B1 and CYP39A1 oxysterol 7␣-hydroxylases, together with their substrate preferences, may thus underlie differences in bile acid metabolism that exist between male and female mice (26,27).…”

Cross-talk between Thyroid Hormone Receptor and Liver X Receptor Regulatory Pathways Is Revealed in a Thyroid Hormone Resistance Mouse Model

“…Pool size was determined as the total bile acid content of small intestine, gallbladder, and the liver, combined as described (25). These organs were homogenized in 20 ml of ethanol (at 60°C), the extract was filtered and a 1-ml aliquot dried with a centrifuge concentrator at room temperature.…”