Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Abstract

Administration of the synthetic estrogen ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,173diol) decreases hepatic Na+,K+-ATPase (ATP phosphohydrolase; EC 3.6.1.3) activity and bile flow to 50% and alters the composition and structure of surface membrane lipid in rats. Although the content of phospholipids was not changed by treatment, free cholesterol (130%) and cholesterol esters (400%) were increased in liver surface membrane fractions. These observations correlate with changes in membrane viscosity, as shown by electron spin resonance probes. Both rotational correlation time, using the isotropic probe methyl (12-nitroxyl)stearate, and the order parameter, determined by the anisotropic probe 5-nitroxylstearic acid, were significantly increased in liver surface membrane fractions from rats treated with ethinyl estradiol. Administration of Triton WR-1339, a nonionic detergent that corrects hepatic and serum lipid changes caused by ethinyl estradiol treatment, restored toward normal elevated membrane lipids and viscosity as well as Na+,K+-ATPase activity and bile flow. Although restoration of normal liver surface membrane structure and function may be due to reversal of abnormal lipid composition, detergents also may directly alter membrane enzyme activity. Addition of Triton WR-1339 in vitro increased Na+,K+-ATPase activity and reduced membrane viscosity of surface membranes from rats treated with ethinyl estradiol. Triton had no effect on either parameter in normal membrane preparations. Studies of membrane structure and function both in vivo and in vitro suggest that alterations in lipid composition may alter Na+,K+-ATPase function and bile flow. Na+,K+-ATPase (ATP phosphohydrolase, EC 3.6.1.3) is a mammalian surface membrane that is sensitive to the lipid structure of the membrane bilayer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)). An important function of Na+,K+-ATPase in the hepatocyte may be the active secretion of sodium into the bile canaliculus, thus driving water across the canalicular membrane (8,9). This fraction has been called bile salt-independent bile flow, and recent studies have demonstrated a strong correlation between hepatic Na+, K+-ATPase activity and bile flow (10), supporting the hypothesis that this component of bile flow is regulated by the sodium pump. One drug consistently shown to reduce bile salt-independent bile flow is the synthetic estrogen derivative ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,17f3-diol) (10)(11)(12)(13).The aim of the present study was to examine whether Na+, K+-ATPase activity is reduced after ethinyl estradiol treatment and, if so, what possible mechanisms might be involved. We recently found that ethinyl estradiol significantly increases hepatic cholesterol ester concentrations by activating hepatic microsomal cholesterol acyl-CoA transferase (14).The possibility that altered membrane lipid composition was involved in the mechanism through which ethinyl estradiolThe publication costs of this article were defrayed in part by page charge payment. Thi...

Beneficial Effects of Silymarin on Estrogen–Induced Cholestasis in the Rat: A Study In Vivo And in Isolated Hepatocyte Couplets

“…Whether this effect reflects modulatory changes of the transporters themselves or whether they occur at the canalicular membrane level, in which these transporters are inserted, remains to be ascertained. Reversion by SIL of EE-induced rigidization of hepatocellular plasma membrane, as indicated by the increase in DPH fluorescence anisotropy (r) induced by EE reported here and by other laboratories, 57,58 can be ruled out as a causal factor. In fact, SIL decreased rather than increased plasma membrane fluidity so that, when administered together with EE, an additive, rigidizing effect was recorded.…”

Protoporphyrin-induced Cholestasis in the Isolated In Situ Perfused Rat Liver

“…Recent investigations suggest that the regulation of BAIF of bile flow may be governed by a multiplicity of complex, interdependent factors including liver plasma membrane NaK ATPase (54-56), bile acids (57,58), canalicular membrane fluidity and viscosity (59,60), and the microfilament apparatus of the canalicular secretory system (61). In this regard, a decrease in liver surface membrane NaK and Mg ATPase activity in protoporphyrin-perfused livers has recently been observed (62).…”

Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat

“…1 Although EE-induced cholestasis has been claimed to represent a model of cholestasis of pregnancy in humans, 2 the mechanism(s) underlying the reduction in bile flow have not been defined. Suggestions that increased permeability of tight junctions 3,4 and reduced activity of Na ϩ / K ϩ -adenosine triphosphatase (ATPase) at the sinusoidal membrane [5][6][7] represent primary events in the onset of cholestasis could not be substantiated in more recent studies. [8][9][10][11] Likewise, the relevance of the reported decrease in sinusoidal membrane fluidity after EE treatment remains questionable, because decreased membrane fluidity has also been found in experimental conditions associated with increased bile flow.…”