Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Abstract

Hepatic 7␣-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7␣-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7␣-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7␣-hydroxylase activity (4 -5-fold) and bile salt secretion (ϳ3-fold). Derepression of hepatic 7␣-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7␣-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7␣-hydroxylase expression at the level of the hepatocyte.Conversion of cholesterol to bile salts is the principal regulated pathway whereby cholesterol is eliminated from the body. The first and rate-limiting step in this pathway is catalyzed by hepatic cholesterol 7␣-hydroxylase (1). Hepatic 7␣-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation (2, 3). Thus, interventions that accelerate bile salt loss from the enterohepatic circulation (thereby reducing bile salt pool size) lead to derepression of hepatic 7␣-hydroxylase expression and enhanced bile salt synthesis. Conversely, expansion of the enterohepatic pool of bile salts leads to suppression of 7␣-hydroxylase activity and reduced rates of bile salt formation.How bile salts fluxing through the enterohepatic circulation regulate the expression of hepatic 7␣-hydroxylase remains unclear. In the bile-diverted rat, depletion of the enterohepatic pool of bile salts leads to derepression of hepatic 7␣-hydroxylase activity and an increase in the rate of bile salt synthesis, effects that can be prevented by the intraduodenal administration of bile salts (4, 5). The conventional interpretation of these experiments is that the flux of bile salts through the hepatocyte (or, more likely, the concentration of bile salts within the hepatocyte) is being sensed, resulting in feedback repression of the rate-limiting enzyme in the bile salt biosynthetic pathway. However, early studies using hepatocyte suspensions or cultures failed to demonstrate any direct regulatory effect of exogenous bile salts on the secretion of bile salts into the media (6, ...

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

“…In contrast, when higher doses were infused, chenodeoxycholate synthesis was inhibited more dramatically. This short-term feedback control is in accordance with Spady' s findings in hamsters, 2 but could not be shown in rats. 42 Most likely, this short-term inhibition is the result of a parallel down-regulation 38 of both cholesterol 7␣-2 and of 27-hydroxylase, because the latter enzyme activity dominates in hamsters, 62 and chenodeoxycholate is assumed to be a main end-product of this acidic pathway.…”

“…44,57 Bile acid infusions did not significantly decrease biliary secretion of de novo cholesterol, suggesting that inhibition of cholesterol synthesis by bile acids may not be relevant in hamsters under these circumstances. 2,58 With prolonged interruption of the enterohepatic circulation, the proportion of biliary cholesterol derived from de novo synthesis was stimulated 6-fold in control animals, reflecting increased cholesterol synthesis, 56 as well as the accumulation of tritium-labeled cholesterol synthesized during the experiment. 44,45 Inhibition of biliary de novo cholesterol secretion was observed only for supraphysiological doses of cholate, most likely by inhibiting cholesterol synthesis late during the experiment.…”

“…This is based on the assumption that a stimulation of cholesterol synthesis is unlikely under these conditions. 2 Therefore, a slightly decreased total synthesis of cholate may be explained by an enhanced but limited availability of de novo cholesterol compensating for a reduced cholate formation from preformed cholesterol. In contrast, chenodeoxycholate synthesis was diminished short term in a dose-dependent manner.…”

“…30,31 Unfortunately, from those studies, no physiologically relevant conclusions may be drawn because of supraphysiological doses and of microbial intestinal conversion of primary to secondary bile acids. Spady et al 2 showed a direct negative feedback control of cholesterol 7␣-hydroxylase activity by primary bile salts at the level of the hepatocyte without an influence on cholesterol synthesis and lowdensity lipoprotein (LDL) receptor activity in the liver, but secondary bile acids were not used.…”

Overexpression of Human Diacylglycerol Acyltransferase 1, Acyl-CoA:Cholesterol Acyltransferase 1, or Acyl-CoA:Cholesterol Acyltransferase 2 Stimulates Secretion of Apolipoprotein B-containing Lipoproteins in McA-RH7777 Cells

“…Thus, despite the conflicting data derived from studies of ACAT inhibitors, increased ACAT activity and the concomitant increase in hepatic CE content are important stimuli for the assembly and secretion of lipid-enriched apoB-lipoproteins. Our data are consistent with the in vivo studies of Spady et al (58) in which increased apoB-lipoprotein secretion resulted from adenoviralmediated increases in hepatic ACAT1 activity. However, consistent with the ACAT2 mutant mouse model, ACAT2 was more efficient in promoting the secretion of VLDL from McA-RH7777 cells.…”