Insulin is a dominant suppressor of sterol 12 alpha-hydroxylase P450 (CYP8B) expression in rat liver: Possible role of insulin in circadian rhythm ofCYP8B

Sterol 12 alpha-hydroxylase (CYP8B) is a key enzyme for regulating the chol ic acid/chenodeoxycholic acid ratio in bile acid biosynthesis, The hepatic CYP8B level was elevated in streptozotocin-induced diabetic rats, and the e levated CYP8B was suppressed by insulin administration [Ishida, H. et al, ( 1999) J, Biochem. 126, 19-25]. The streptozotocin-induced elevation of hepa tic CYP8B mRNA concomitantly responded to the decrement of the serum insuli n level. The CYP8B mRNA level in the cultivated rat hepatoma H4TG cells was strongly suppressed by insulin, although it was affected by dibutyryl cAMP or thyroxine to lesser extents. These observations demonstrate that CYP8B expression is dominantly regulated by the direct action of insulin on hepat ocytes, A marked circadian rhythm (maximum at 13:00-16:00 and minimum at 1: 00) was observed both on the mRNA level and the activity of CYP8B, This rhy thm was shifted from that of cholesterol 7 alpha-hydroxylase, a rate-limiti ng enzyme of bile acid biosynthesis, showing a maximum at 22:00 and a minim um at 10:00, and this shift might oscillate the cholic acid/chenodeoxycholi c acid ratio, which is increased in the late afternoon and decreased at mid night. The rhythm of CYP8B was the inverse of the circadian variation of se rum insulin level and was similar to the circadian rhythm of glucose 6-phos phatase. These facts and the potent suppressive effect of insulin on CYP8B indicate that the oscillation of the serum insulin may be a factor in produ cing the circadian rhythm of CYP8B.