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Research Article

The Normal Mechanisms of Pregnancy-induced Liver Growth are Not Maintained in Mice Lacking the Bile Acid Sensor Fxr

^{1 2}King's College London ³Imperial College ⁴Imperial College, London

Submitted 13 August 2009 ; revision received 30 September 2009 ; accepted in final form 1 October 2009

ABSTRACT

Rodents undergo gestational hepatomegaly in order to meet the increased metabolic demands on the maternal liver during pregnancy. This is an important physiological process but the mechanisms and signals driving pregnancy-induced liver growth are not known. Here, we show that liver growth during pregnancy precedes maternal body weight gain, is proportional to fetal number and is a result of hepatocyte hypertrophy associated with cell-cycle progression, polyploidy and altered expression of cell-cycle regulators p53, Cyclin-D1 and p27. Because circulating reproductive hormones and bile acids are raised in normal pregnant women and can cause liver growth in rodents, these compounds are candidates for the signal driving gestational liver enlargement in rodents. Administration of pregnancy levels of reproductive hormones was not sufficient to cause liver growth but mouse pregnancy was associated with increased serum bile acid levels. It is known that the bile acid sensor Fxr is required for normal recovery from partial hepatectomy and we demonstrate that Fxr^-/- mice undergo gestational liver growth by adaptive hepatocyte hyperplasia. This is the first identification of any component that is required to maintain the normal mechanisms of gestational hepatomegaly and also implicates Fxr in a physiologically normal process that involves control of the hepatocyte cell-cycle. Understanding pregnancy induced hepatocyte hypertrophy in mice could suggest mechanisms for safely increasing functional liver capacity in women during increased metabolic demand.

Cholestasis; Bile acids; Liver regeneration; Cell-cycle