Cholesterol 7?-hydroxylase (CYP7A): Patterns of messenger RNA expression during rat liver development

Abstract

Cholesterol 7␣-hydroxylase is a rate-limiting enzyme in bile acid synthesis, a major pathway for cholesterol catabolism. It plays a crucial role in postnatal development and survival. In an adult liver, its activity and messenger RNA (mRNA) are heterogeneously distributed with concentration in the pericentral area. We defined how the pattern of cholesterol 7␣-hydroxylase mRNA evolves during rat liver development, correlated this with its total liver mRNA levels, and determined when its heterogeneous pattern of expression is established. Cholesterol 7␣-hydroxylase mRNA was undetectable in 18-day-old fetal livers by Northern blot. It was increased markedly in newborns with a homogeneous liver lobular distribution as determined by in situ hybridization. At postnatal day four, mRNA levels were markedly decreased with concomitant appearance of a lobular gradient: mRNA was detected only in a few hepatocytes located around efferent venules. At 22 days, the time of highest mRNA expression, a marked extension of the gradient towards the periportal area was observed, indicating that the increase in total liver cholesterol 7␣-hydroxylase mRNA level was a result of recruitment of hepatocytes upstream from the central vein area. By 28 days, the adult pattern was observed. Thus, expression of cholesterol 7␣-hydroxylase mRNA is tightly regulated during rat liver development, both temporally and spatially supporting its critical role in normal postnatal development.(HEPATOLOGY 1998;28:1064-1072.)Bile acids play a key role in absorption of lipids, including fat-soluble vitamins. Bile acid synthesis represents the major regulated pathway for catabolism and excretion of cholesterol in mammals. The hepatospecific enzyme cholesterol 7␣-hydroxylase (C7␣H; EC 1.14.13.17; CYP7A) catalyzes a rate-limiting step in this important process. [2][3][4] Its activity is tightly regulated in vivo by a number of different effectors acting predominantly at the transcriptional level. C7␣H is modulated by hormones, including thyroxin, glucocorticoids, and insulin 5-7 ; and by dietary factors. [8][9][10] It is regulated in a negative feedback manner by hydrophobic bile acids returning to the liver via the enterohepatic circulation. 11-13 It exhibits a diurnal rhythm, with maximum activity in the dark phase and minimum during the light phase in rats. [13][14][15] The expression of C7␣H in adult rats is tightly regulated spatially along the liver cell plate; the enzymatic activity 16 and mRNA level 17,18 are not distributed uniformly among parenchymal cells; rather, C7␣H is predominantly found in a subgroup of hepatocytes localized around the central vein.Liver cell heterogeneity is considered to be a major determinant for proper execution and regulation of most liver functions. 19,20 It reflects differentiation of hepatocytes within the liver plate, which is established during development. In most cases, it is regulated at the transcriptional level. The role of liver cell heterogeneity in the developmental regulation of bile acid synthesis is unknown....

Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development

“…Thus the nearadult expression of FXR at day P7 is consistent with 90% expression of Bsep mRNA, which is activated by FXR, as observed by us (31) and confirmed by Gao et al (8) (123% of adult at day P5) using real-time PCR, as well as the decreased expression of cyp7a1 (23) at this stage of liver development. However, it cannot explain the adult-level expression of Ntcp mRNA at day P7 (11), suggesting the participation of other mechanisms in its regulation.…”

“…3) is at 39.4% of the adult on day P7. These data are consistent with undetectable cyp7a1 mRNA at day E18, a rise in the newborn followed by a decrease at day P4 and reaching adult levels at age P22 days in rat liver as reported by Massimi et al (23). These values may also explain the need for bile acid supplementation of diet of cyp7a1-null mice during the immediate postnatal period due to immaturity of alternative bile acid synthetic pathways (13).…”

Transgenic expression of CYP7A1 in LDL receptor-deficient mice blocks diet-induced hypercholesterolemia

“…Normally, CYP7A1 is expressed in only a "few" parenchymal cells located in the pericentral zone of the liver acinus (31). Expression of CYP7A1 mRNA changes rapidly (half-life of mRNA , 0.5 min (32)] and varies widely in response to diet, diurnal cycle, and changes in the size of the bile acid pool (reviewed in 1).…”

Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice

“…Under normal circumstances, CYP7A1 is expressed only in the liver (6). It shows a unique developmental pattern of expression (12,13) and a unique liver lobular distribution in the adult (13,14). Its regulation is complex [as reviewed in refs.…”