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LIVER AND BILIARY TRACT

High levels of caveolar cholesterol inhibit progesterone-induced genomic actions in human and guinea pig gallbladder muscle

Departments of ¹Medicine and ²Surgery of the Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island

Submitted 15 December 2008 ; accepted in final form 30 January 2009

Gallbladder disease is prevalent during pregnancy. It has been suggested that this complication of pregnancy is attributable to increased bile cholesterol (Ch) induced by estrogens and to gallbladder hypomotility caused by increasing levels of progesterone (P4). Studies on nonpregnant gallbladders have shown that increased levels of bile Ch contribute to both gallstone formation and bile stasis. These studies investigated the effects of high levels of plasma membrane Ch on P4 on gallbladder muscle cells from human and guinea pigs. Contraction was studied in intact and permeabilized muscle cells. G proteins were determined by Western blot, and ³H-P4 incorporation by muscle cells was measured in the β-scintillation counter. High levels of caveolar Ch blocked the effects induced by P4 treatment for 6 h. They suppressed the expected P4 inhibition of GTP-S (a G protein activator)-induced contraction and changes in G proteins by downregulating Gi3 and upregulating Gs protein levels. Ch inhibited these P4 actions at the caveolar 3 (CAV-3) level, since the P4 effects were antagonized by treatment with CAV-3 antibody, by reducing CAV-3 expression through CAV-3 siRNA. CAV-3 antibody and siRNA reduced caveolar Ch levels. High caveolar levels of Ch and CAV-3 antibody blocked the incorporation of ³H-P4 into caveolae. Treatment with GDP-βS (a G protein antagonist) had no effect on P4 actions. High caveolar Ch levels blocked the P4 effects on muscle contraction and G protein changes probably because both Ch and P4 require CAV-3 proteins for their transport across the plasma membrane.

muscle cells; caveolar 3 proteins; G proteins

This article has been cited by other articles:

				Z. L. Xiao, P. Biancani, and J. Behar Effects of progesterone on motility and prostaglandin levels in the distal guinea pig colon Am J Physiol Gastrointest Liver Physiol, November 1, 2009; 297(5): G886 - G893. [Abstract] [Full Text] [PDF]