Anticholestatic mechanisms of ursodeoxycholic acid in lipopolysaccharide-induced cholestasis

Abstract

Lipopolysaccharide (LPS) from Gram (-) bacteria induces inflammatory cholestasis by impairing the expression/localization of transporters involved in bile formation (e.g., Bsep, Mrp2). Therapeutic options for this disease are lacking. Ursodeoxycholic acid (UDCA) is the first choice therapy in cholestasis, but its anticholestatic efficacy in this hepatopathy remains to be evaluated. To asses it, male Wistar rats received UDCA for 5 days (25 mg/Kg/day, i.p.) with or without LPS, administered at 8 a.m. of the last 2 days (4 mg/Kg/day, i.p.), plus half of this dose at 8 p.m. of the last day. Then, plasma alkaline phosphatase (ALP), bile flow, basal and taurocholate-stimulated bile acid output, total glutathione output, and total/plasma membrane liver protein expression of Bsep and Mrp2 by confocal microscopy were assessed. mRNA levels of both transporters were assessed by Real-time PCR. Plasma pro-inflammatory cytokines (IL-6 and TNF-α) were measured by ELISA. Our results showed that, UDCA attenuated LPS-induced ALP plasma release and the impairment in the excretion of the Bsep substrate, taurocholate. This was associated with an improved Bsep expression at both mRNA and protein levels, and by an improved localization of Bsep in plasma membrane. UDCA failed to reduce the increase in plasma pro-inflammatory cytokines induced by LPS and Mrp2 expression/function. In conclusion, UDCA protects the hepatocyte against the damaging effect of bile acids accumulated by the LPS-induced secretory failure. This involved an enhanced synthesis of Bsep and an improved membrane stability of the newly synthesized transporters.

The effects of ursodeoxycholic acid in the management of sepsis-induced cholestasis in rodents

“…There was no effect for UDCA on either IL-1α or IL-4. This is consistent with the report of Razori et al (24) who found that attenuation in TNF-α and IL-6 cytokines in LPS treated rats was not statically significant. Also, Diamond et al (25) showed the lack of effect of UDCA in reducing the expression of cytokines.…”

Preclinical evidence of Yinchenhao decoction on cholestasis: A systematic review and meta‐analysisof animal studies

“…Currently, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only drugs approved by the United States Food and Drug Administration for cholestasis (Cabrera, Arab, & Arrese, 2019). Early treatment can alleviate symptoms, improve liver enzyme abnormalities and reduce mortality in patients with primary biliary cirrhosis (PBC; Razori et al, 2019). However, UDCA is used for early PBC and one‐third of affected patients show no response to it.…”

“…Early treatment can alleviate symptoms, improve liver enzyme abnormalities and reduce mortality in patients with primary biliary cirrhosis (PBC; Razori et al, 2019). However, UDCA is used for early PBC and one-third of affected patients show no response to it.…”

Spironolactone ameliorates lipopolysaccharide-induced cholestasis in rats by improving Mrp2 function: Role of transcriptional and post-transcriptional mechanisms

“…In a previous work [10], we studied the anti-cholestatic effects of ursodeoxycholic acid (UDCA) in LPS-induced cholestasis, as it is the "first choice" therapeutic approach for most cholestatic hepatopathies. Since its beneficial effects were partial, we decided to evaluate spironolactone (SL) as a complementary anti-cholestatic agent, which could act via alternative pathways.…”

“…The time-course of the changes in the biliary output of the exogenously administered Bsep and Mrp2 solutes TC [10] and DBSP [22], respectively, have been assessed to estimate in vivo the transport efficiency of these canalicular carriers. Despite uptake of these solutes may be affected by LPS treatment [23], this process is unlikely to significantly influence biliary excretion, because 1) canalicular transfer but not basolateral uptake is the rate-limiting step in the hepatic handling of cholephilic compounds [24], and 2) kinetic studies suggest that the ABC canalicular transporters work under Tm conditions [25], so that changes in intracellular levels due to impaired uptake should have negligible, if any effect on biliary excretion; this situation is unlikely…”