Abstract
The effects of four bile acids on cell Ca2+ were examined in suspensions of isolated rat hepatocytes. Taurolithocholate and lithocholate which inhibit bile secretion increased the cytosolic Ca2+ concentration (ED50, 25 microM), as measured by the fluorescent indicator quin2, and promoted a net loss of Ca2+ from the cells. This effect resulted from rapid mobilization of Ca2+ from an intracellular Ca2+ store. This store corresponds to the one that is permeabilized by the inositol (1,4,5)trisphosphate-dependent hormone vasopressin. However, taurolithocholate and lithocholate, unlike the hormone, did not induce a significant accumulation of inositol trisphosphate fraction in isolated hepatocytes. In addition, these agents did not alter the cell and the mitochondria membrane permeability to ions. When applied to saponin-permeabilized cells, taurolithocholate and lithocholate released Ca2+ (ED50, 20 microM) from an ATP-dependent, nonmitochondrial pool which is sensitive to inositol (1,4,5)trisphosphate. In contrast, the bile acids taurocholate and cholate, which increase bile secretion, had no effect on cell Ca2+ in intact hepatocytes or in saponin-permeabilized hepatocytes. It is suggested that taurolithocholate and lithocholate permeabilize the endoplasmic reticulum to Ca2+ and that the resulting permeabilization of this compartment may be involved in the inhibition of bile secretion in mammalian liver.
Highlights
The effects of four bile acids on cell Ca2+were ex- stimulation of the Ca2+influx
Taurocholic acid and cholic acid have no effect on cell Ca2+.This is the firstdemonstration thatthe monohydroxylated bile acids permeabilize selectively the endoplasmic reticulum (ER) to Ca2+.It is suggested that this permeabilization of the ER to Ca2+could be at theorigin of the inhibition of bile secretion induced by these agents
In quin2 and quin2-tetraacetoxymethylester from Lancaster Synthesis, contrast, the bile acids taurocholate and cholate, which ionomycin from Behring Diagnostics, and Ins[1,4,5]P3 from Amerincrease bile secretion, had no effect on cell Ca2+in intact hepatocytes or in saponin-permeabilized hepatocytes
Summary
Thedose-response curve in low Ca media (ED,, = 26 p ~wa) s not different from that in normal Ca2+media (ED5, = 22 p ~ )P.rolonged incubation with EGTA or preincubation of the cells in a medium without added CaZ+ (2-10 min) produced a time-dependent decrease of the amplitude of tbe This is in good agreement with the observation of the decrease of the internal. These results areconsistent with a primary action of TLC and lithocholic acid on the internal CaZ+ storeosf the hepatocyte
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