Polycystic Liver Disease: The Benefits of Targeting cAMP

LaRusso, Nicholas F.; Masyuk, Tatyana V.; Hogan, Marie C.

doi:10.1016/j.cgh.2016.03.008

Cited by 17 publications

(17 citation statements)

References 20 publications

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“…Increased intracellular cAMP levels have been reported in cystic cholangiocytes and serum of PCK rats and Pkd2cKO mice [18,24,25] , and seem to be a general pathologic event occurring in all forms of PLD [2] . cAMP differentially regulates the proliferation and secretion of normal and cystic cholangiocytes [11] .…”

Section: Camp and Ca 2+ Signalling In Pldsmentioning

confidence: 99%

Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment

Labiano¹,

Esparza-Baquer²,

Marzioni³

et al. 2017

Dig Dis

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Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.

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Section: Camp and Ca 2+ Signalling In Pldsmentioning

confidence: 99%

Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment

Labiano¹,

Esparza-Baquer²,

Marzioni³

et al. 2017

Dig Dis

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“…Patients may experience constant abdominal pain and distension and may develop multiple complications such as cyst hemorrhage, rupture, or infection. 1,2 The treatment goal in PLD is liver volume reduction to ameliorate symptoms. Interventional therapies include hepatic resection, liver transplantation, cyst aspiration, sclerosis, or fenestration.…”

mentioning

confidence: 99%

“…Interventional therapies include hepatic resection, liver transplantation, cyst aspiration, sclerosis, or fenestration. 1,2,5 Currently, somatostatin receptor (SSTR) analogues, such as octreotide and lanreotide, are the only available pharmacologic option for PLD patients. However, despite their beneficial effects on hepatic cystogenesis and quality of life, changes in liver volume are modest, and approximately 15% of patients are nonresponders.…”

mentioning

confidence: 99%

Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease

Pisarello

Masyuk

Gradilone

et al. 2018

The American Journal of Pathology

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Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide. We also assessed effects of ACY-1215 and pasireotide alone and in combination on cell proliferation, cAMP production, and expression of acetylated α-tubulin in vitro in cultured cholangiocytes and the length of primary cilia and the frequency of ciliated cholangiocytes in vivo in PCK rats. Panobinostat and all three HDAC6 inhibitors decreased hepatorenal cystogenesis in PCK rats. ACY-1215 was more effective than other HDAC inhibitors and was chosen for combinational treatment. ACY-1215 + pasireotide combination synergistically reduced cyst growth and increased length of primary cilia in PCK rats. In cultured cystic cholangiocytes, ACY-1215 + pasireotide combination concurrently decreased cell proliferation and inhibited cAMP levels. These data suggest that the combination of drugs that inhibit HDAC6 and cAMP may be an effective therapy for PLD.

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“…Indeed, we have shown that suppression of cAMP in cystic cholangiocytes by octreotide and pasireotide, synthetic octapeptide agonists of somatostatin receptors (SSTRs), inhibited hepatic cystogenesis in animal models of PLD . Moreover, octreotide decreased liver volume (by ∼5%) in patients with PLD and improved quality of life . While somatostatin analogues are considered to be the only available drug option, treatment is costly ($7,000‐$11,000 per month), changes in liver volume are modest, up to 15% of patients do not respond to treatment, and after drug withdrawal the liver volume returns to pretreatment levels .…”

mentioning

confidence: 99%

“…(4,9) Moreover, octreotide decreased liver volume (by 5%) in patients with PLD and improved quality of life. (10)(11)(12) While somatostatin analogues are considered to be the only available drug option, treatment is costly ($7,000-$11,000 per month), changes in liver volume are modest, up to 15% of patients do not respond to treatment, and after drug withdrawal the liver volume returns to pretreatment levels. (11) Thus, a search for new therapeutic options remains of great importance.…”

mentioning

confidence: 99%

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling

Masyuk¹,

Masyuk²,

Pisarello³

et al. 2017

Hepatology

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Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA-treated PCK rats and after genetic elimination of TGR5 in double mutant TGR5−/−;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2–3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation and cyst growth by ~40%; these effects were abolished after TGR5 reduction by shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its co-localization with Gαs were increased ~2-fold upon OA treatment. Levels of cAMP, cell proliferation and cyst growth in vitro were decreased by ~30% in cystic cholangiocytes after treatment with SBI-115 alone and by ~50% when SBI-115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation. Our data suggest that a TGR5 antagonist alone or concurrently with SSTR agonists represents novel therapeutic approaches in PLD.

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Polycystic Liver Disease: The Benefits of Targeting cAMP

Cited by 17 publications

References 20 publications

Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment

Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment

Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling

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