The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury

Abstract

BackgroundWe previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R.Material and methodsMale Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured.ResultsOCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression.ConclusionThe reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.

Obeticholic acid reduces biliary and hepatic matrix metalloproteinases activity in rat hepatic ischemia/reperfusion injury

“…Moreover, a similar trend occurred for markers of cholangiocyte injury (LDH and γGT) and cholangiocyte function (glucose) [ 27 ] in the I/R group treated with OCA. These events are associated with the ability of OCA to increase biliary ADMA via MATE-1 upregulation, the latter a canalicular efflux transporter involved in ADMA clearance [ 6 ]. Although no published data on biliary content in MMPs and ADMA have been reported, the correlation between biliary MMPs and cholangiocyte injury and the correlation between biliary ADMA and MMPs suggest that both MMPs and ADMA levels could play a crucial role in the modulation of cholangiocyte integrity during I/R damage.…”

“…We recently documented, in a model of rat ischemia/reperfusion (I/R) injury, the ability of OCA to upregulate the biliary excretion of asymmetric dimethylarginine (ADMA), a potent inhibitor of constitutive and inducible nitric oxide synthase (NOS) [ 6 ]. We also demonstrated OCA’s ability to decrease iNOS content.…”

Asymmetric (ADMA) and Symmetric (SDMA) Dimethylarginines in Chronic Kidney Disease: A Clinical Approach

“…The role of a specific drug, the farnesoid X receptor agonist GW 4064, is being investigated, given its ability to increase the expression of DDAH and decrease ADMA levels [114]. The farnesoid X receptor agonist increases biliary excretion of ADMA during hepatic ischemia/reperfusion injury [115].…”

Farnesoid X Receptor Activation Protects Liver From Ischemia/Reperfusion Injury by Up‐Regulating Small Heterodimer Partner in Kupffer Cells

“…Our study demonstrates that pharmacologic activation of FXR protects liver from IRI at both acute and recovery stages. Although FXR agonists have been shown to protect multiple organs from IRI in the heart, intestine, kidney, and liver models and modulate liver inflammation in non‐IRI models, cellular targets of FXR activation and immune regulatory mechanisms have not been well defined. Our results showed that the FXR‐targeted gene SHP was critical for the therapeutic effect of FXR activation in liver IRI.…”

“…FXR activation by its agonists, such as 3‐(2,6‐dichlorophenyl)‐4‐(3′‐carboxy‐2‐chlorostilben‐4‐yl)oxymethyl‐5‐isopropylisoxazole (GW4064) and 6α‐ethyl‐chenodeoxycholic acid (6α‐ECDCA), protected small intestine and kidneys from IRI and attenuated local inflammatory responses . In liver, obeticholic acid (OCA) marginally reduced IRI in a rat model . In the current study, we explored the therapeutic potential of pharmacologic FXR activation and the underlying mechanism in the pathophysiology of liver IRI in a murine model of partial hepatic warm ischemia.…”