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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #168382
Title: RESISTANCE OF SHP-NULL MICE TO BILE ACID-INDUCED LIVER DAMAGE.

Author
item WANG, L - BAYLOR COLL OF MEDICINE
item HAN, Y - BAYLOR COLL OF MEDICINE
item KIM, C - BAYLOR COLL OF MEDICINE
item LEE, Y - BAYLOR COLL OF MEDICINE
item MOORE, D - BAYLOR COLL OF MEDICINE

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/20/2003
Publication Date: 11/1/2003
Citation: Wang, L., Han, Y., Kim, C.S., Lee, Y.K., Moore, D.D. 2003. Resistance of SHP-null mice to bile acid-induced liver damage. Journal of Biological Chemistry. 278(45):44475-81.

Interpretive Summary: This manuscript describes an unexpected effect of bile acids in mice lacking the gene for SHP, which functions to regulate bile acid production. In contrast to expectations, these mice are less sensitive to toxic effects of high levels of bile acids in the diet.

Technical 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 12 alpha-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 7 alpha-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.