Abstract
The orphan nuclear hormone receptor SHP (gene designation NROB2) is an important component of a negative regulatory cascade by which high levels of bile acids repress bile acid biosynthesis. Short term studies in SHP null animals confirm this function and also reveal the existence of additional pathways for bile acid negative feedback regulation. We have used long term dietary treatments to test the role of SHP in response to chronic elevation of bile acids, cholesterol, or both. In contrast to the increased sensitivity predicted from the loss of negative feedback regulation, the SHP null mice were relatively resistant to the hepatotoxicity associated with a diet containing 0.5% cholic acid and the much more severe effects of a diet containing both 0.5% cholic acid and 2% cholesterol. This was associated with decreased hepatic accumulation of cholesterol and triglycerides in the SHP null mice. There were also alterations in the expression of a number of genes involved in cholesterol and bile acid homeostasis, notably cholesterol 12alpha-hydroxylase (CYP8B1), which was strongly reexpressed in the SHP null mice, but not the wild type mice fed either bile acid containing diet. This contrasts with the strong repression of CYP8B1 observed with short term bile acid feeding, as well as the effects of long term feeding on other bile acid biosynthetic enzymes such as cholesterol 7alpha-hydroxylase (CYP7A1). CYP8B1 expression could contribute to the decreased toxicity of the chronic bile acid treatment by increasing the hydrophilicity of the bile acid pool. These results identify an unexpected role for SHP in hepatotoxicity and suggest new approaches to modulating effects of chronically elevated bile acids in cholestasis.
Highlights
Cholesterol conversion to bile acids occurs via two different pathways: the classic and the alternative pathways, the end products of which are cholic acid and chenodeoxycholic acid
Diminished Hepatomegaly in SHP-deficient Mice—Recent results demonstrate that SHP has a crucial role in the acute negative feedback regulation of bile acid biosynthesis in vivo [20, 21]
Previous short term studies (1 day to 1 week) of the effects of bile acids and synthetic FXR agonists on wild type and SHP knockout mice established the important role of this unusual orphan nuclear receptor in the negative feedback regulation of bile acid biosynthesis [20, 21]
Summary
Cholesterol conversion to bile acids occurs via two different pathways: the classic and the alternative pathways, the end products of which are cholic acid and chenodeoxycholic acid. When hepatic cholesterol levels are high, oxysterols accumulate and activate the LXRs, which stimulate the transcription of CYP7A1 [12, 13] This results in increased bile acid synthesis and the subsequent excretion of cholesterol. BAs are transported to the canalicular membrane by the intracellular BA-binding protein L-FABP (liver fatty acid-binding protein), 3␣-HSD (3␣-hydroxysteroid dehydrogenase), and GST (glutathione S-transferase) isoforms They are excreted from the hepatocyte by the bile salt export pump BSEP and the multidrug-resistance-associated protein Mrp. BAs are released from the gallbladder into the intestine where they are reabsorbed by enterocytes, primarily in the ileum This process depends on ASBT for import, the cytosolic intestinal BA-binding protein I-BABP for intracellular transport, and basolateral Mrp for export into the portal circulation. Defects in the expression or transcriptional and post-transcriptional regulation of components of this enterohepatic BA transporter pathway have been recognized as important causes for various cholestatic liver diseases [27]
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