Alternate pathways of bile acid synthesis in the cholesterol 7α-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding

Margrit Schwarz,David W Russell,John M Dietschy,Stephen D Turley

doi:10.1016/s0022-2275(20)32213-6

Margrit Schwarz, David W Russell + Show 2 more

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https://doi.org/10.1016/s0022-2275(20)32213-6

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Abstract

Bile acids are synthesized via the classic pathway initiated by cholesterol 7α-hydroxylase (CYP7A1), and via alternate pathways, one of which is initiated by sterol 27-hydroxylase (CYP27). These studies used mice lacking cholesterol 7α-hydroxylase (Cyp7a1−/−) to establish whether the loss of the classic pathway affected cholesterol homeostasis differently in males and females, and to determine if the rate of bile acid synthesis via alternate pathways was responsive to changes in the enterohepatic flux of cholesterol and bile acids. In both the Cyp7a1−/− males and females, the basal rate of bile acid synthesis was only half of that in matching Cyp7a1+/+ animals. Although bile acid pool size contracted markedly in all the Cyp7a1−/− mice, the female Cyp7a1−/− mice maintained a larger, more cholic acid-rich pool than their male counterparts. Intestinal cholesterol absorption in the Cyp7a1−/− males fell from 46% to 3%, and in the matching females from 58% to 17%. Bile acid synthesis in Cyp7a1+/+ males and females was increased 2-fold by cholesterol feeding, and 4-fold by cholestyramine treatment, but was not changed in matching Cyp7a1−/− mice by either of these manipulations. In the Cyp7a1−/− mice fed cholesterol, hepatic cholesterol concentrations increased only marginally in the males, but rose almost 3-fold in the females. CYP7A1 activity and mRNA levels were greater in females than in males, and were increased by cholesterol feeding in both sexes. CYP27 activity and mRNA levels did not vary as a function of CYP7A1 genotype, gender, or dietary cholesterol intake. We conclude that in the mouse the rate of bile acid synthesis via alternative pathways is unresponsive to changes in the enterohepatic flux of cholesterol and bile acid, and that factors governing gender-related differences in bile acid synthesis, pool size, and pool composition play an important role in determining the impact of CYP7A1 deficiency on cholesterol homeostasis in this species.—Schwarz, M., D. W. Russell, J. M. Dietschy, and S. D. Turley. Alternate pathways of bile acid synthesis in the cholesterol 7α-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. J. Lipid Res. 2001. 42: 1594–1603.

Highlights

Bile acids are synthesized via the classic pathway initiated by cholesterol 7␣-hydroxylase (CYP7A1), and via alternate pathways, one of which is initiated by sterol 27hydroxylase (CYP27)
The study of the quantitative importance and regulability of the alternate pathways of bile acid synthesis is challenging because at least three separate pathways are involved. Most studies of these questions have focused on the pathway initiated by CYP27, which in humans apparently accounts for only about 9% of total bile acid synthesis [11]
The percent contribution of this pathway to bile acid production in other species continues to be investigated. It cannot be determined by deleting the gene for CYP27 because this obstructs the classic pathway, which requires CYP27 for oxidation of the cholesterol side chain [3]

Summary

Introduction

Bile acids are synthesized via the classic pathway initiated by cholesterol 7␣-hydroxylase (CYP7A1), and via alternate pathways, one of which is initiated by sterol 27hydroxylase (CYP27) These studies used mice lacking cholesterol 7␣-hydroxylase (Cyp7a1؊/؊) to establish whether the loss of the classic pathway affected cholesterol homeostasis differently in males and females, and to determine if the rate of bile acid synthesis via alternate pathways was responsive to changes in the enterohepatic flux of cholesterol and bile acids. The 25- and 27hydroxycholesterol intermediates are substrates for oxysterol 7␣-hydroxylase (CYP7B1) [4], whereas 24-hydroxycholesterol is the preferred substrate for another oxysterol 7␣hydroxylase, CYP39A1 [5] Irrespective of their metabolic origin, all 7␣-hydroxylated oxysterols are converted to primary bile acids via several more enzymatic steps that are shared between the classic and alternate pathways.

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