Metabolic preconditioning protects BSEP/ABCB11−/− mice against cholestatic liver injury

Fuchs, Claudia D.; Paumgartner, Gustav; Wahlström, Annika; Schwabl, Philipp; Reiberger, Thomas; Leditznig, Nadja; Stojaković, Tatjana; Rohr-Udilova, Nataliya; Chiba, Peter; Marschall, Hanns‐Ulrich; Trauner, Michael

doi:10.1016/j.jhep.2016.08.017

Cited by 56 publications

(60 citation statements)

References 25 publications

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“…) . In BDL mice and BSEP –/– mice extensive hydroxylation of BS produces tetrahydroxylated BS that can be removed through the urine . These transcriptional and posttranslational changes mainly function to protect hepatocytes against cholestatic injury but not necessarily to protect the biliary tree or the liver against cholestatic injury.…”

Section: Upstream Eventsmentioning

confidence: 99%

“…Moreover, increased luminal pressure due to choleretic effects of ursodeoxycholic acid (UDCA) has been postulated to cause rupture of the canals of Hering and consequently bile leaking into the parenchyma, leading to bile infarcts . A recent study indicates that the increased hydrostatic pressure depends on the presence of Bsep as biliary pressure after BDL did not increase in Bsep –/– mice . Disruptions of tight junctions are known to occur throughout the biliary tree, possibly contributing to the leakiness of bile ducts .…”

Section: The Role Of Intraluminal Biliary Pressurementioning

confidence: 99%

“…(42,43) In BDL mice and BSEP -/mice extensive hydroxylation of BS produces tetrahydroxylated BS that can be removed through the urine. (44) These transcriptional and posttranslational changes mainly function to protect hepatocytes against cholestatic injury but not necessarily to protect the biliary tree or the liver against cholestatic injury. For instance, the expression of Mrp2/MRP2 and Bsep/BSEP in mice and humans during cholestasis helps to remove bile acids and other toxic agents from hepatocytes but contributes to a potentially harmful increase of biliary pressure.…”

Section: Adaptation Of Hepatocytesmentioning

confidence: 99%

“…(49,50) A recent study indicates that the increased hydrostatic pressure depends on the presence of Bsep as biliary pressure after BDL did not increase in Bsep -/mice. (44) Disruptions of tight junctions are known to occur throughout the biliary tree, possibly contributing to the leakiness of bile ducts. (51) Leaky bile ducts could allow exchange between the biliary lumen and sinusoidal blood.…”

Section: Adaptation Of Hepatocytesmentioning

confidence: 99%

“…However, manometric tracing of biliary pressure revealed increases of only approximately 0.74 mm Hg by BDL and a further increase to 1.0 mm Hg by additional feeding of UDCA to BDL mice, similar to the increase of 2 mm Hg recently reported in BDL Bsep 1/1 wild-type mice. (44,50) Considering that blood pressure at the basolateral side of hepatocytes is in the range 6-12 mm Hg, it seems unlikely that the relatively small changes in biliary pressure of 1-2 mm Hg can cause direct mechanical tissue damage in this mouse model unless mechanosensing receptors, sensitive enough to detect small changes in pressure, are present I 0 1I max a 1I max d e ð2t peak =s a Þ 2e ð2t=s a Þ : t t peak I 0 1I max d e 2ðt2t peak Þ=s d : t t peak…”

Section: Adaptation Of Hepatocytesmentioning

confidence: 99%

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The ascending pathophysiology of cholestatic liver disease

Ghallab²,

et al. 2017

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In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in “downstream” bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)–mediated toxic injury of the “upstream” liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom‐poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%‐60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more “tailored” use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium‐dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis–suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti‐inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor‐ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end‐stage disease. These are arguments to consider a step‐wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage–defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722‐738).

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Section: Upstream Eventsmentioning

confidence: 99%

Section: The Role Of Intraluminal Biliary Pressurementioning

confidence: 99%

Section: Adaptation Of Hepatocytesmentioning

confidence: 99%

Section: Adaptation Of Hepatocytesmentioning

confidence: 99%

Section: Adaptation Of Hepatocytesmentioning

confidence: 99%

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The ascending pathophysiology of cholestatic liver disease

Ghallab²,

et al. 2017

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ABC Transporters in Intestinal and Liver Efflux

Morris,

Ren

2023

Oral Bioavailability and Drug Delivery

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New therapeutic concepts in bile acid transport and signaling for management of cholestasis

et al. 2017

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The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA-induced gut hormones, fibroblast growth factor 19 and glucagon-like peptide 1, and the BA transport systems, apical sodium-dependent bile acid transporter and Na -taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393-1404).

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Metabolic preconditioning protects BSEP/ABCB11−/− mice against cholestatic liver injury

Abstract: Reduced hepatobiliary bile acid transport due to loss of BSEP function leads to increased hydroxylation of bile acids in the liver. Metabolic preconditioning with a hydrophilic bile pool protects the BSEP mice from acquired cholestatic liver disease.

Cited by 56 publications

References 25 publications

The ascending pathophysiology of cholestatic liver disease

The ascending pathophysiology of cholestatic liver disease

ABC Transporters in Intestinal and Liver Efflux

New therapeutic concepts in bile acid transport and signaling for management of cholestasis

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