Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease
Patricia Munoz-Garrido, José J G Marin, María J Perugorria, Aura D Urribarri, Oihane Erice, Elena Sáez, Miriam Úriz, Sarai Sarvide, Ainhoa Portu, Axel R Concepcion, Marta R Romero, María J Monte, Álvaro Santos-Laso, Elizabeth Hijona, Raúl Jimenez-Agüero, Marco Marzioni, Ulrich Beuers, Tatyana V Masyuk, Nicholas F LaRusso, Jesús Prieto, Luis Bujanda, Joost P H Drenth, Jesús M Banales, Patricia Munoz-Garrido, José J G Marin, María J Perugorria, Aura D Urribarri, Oihane Erice, Elena Sáez, Miriam Úriz, Sarai Sarvide, Ainhoa Portu, Axel R Concepcion, Marta R Romero, María J Monte, Álvaro Santos-Laso, Elizabeth Hijona, Raúl Jimenez-Agüero, Marco Marzioni, Ulrich Beuers, Tatyana V Masyuk, Nicholas F LaRusso, Jesús Prieto, Luis Bujanda, Joost P H Drenth, Jesús M Banales
Abstract
Background & aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short-term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca(2+)]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated.
Methods: Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated from the liver, bile, serum, and kidneys by HPLC-MS/MS.
Results: Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA.
Conclusions: UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the levels of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients.
Keywords: Cholangiocyte; Cystogenesis; Intracellular calcium; Polycystic liver diseases (PLDs); Therapy; Ursodeoxycholic acid (UDCA).
Conflict of interest statement
Disclosures: authors disclose no conflicts.
Copyright © 2015 European Association for the Study of the Liver. All rights reserved.
Figures
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
Treatment of PCK rats with UDCA halts hepatic cystogenesis and fibrosis, and improves their motor behaviour. (A and B) Representative images (hematoxylineosin staining; 5× magnification in Fig. 1A) and bar graph showing hepatic cysts in untreated and UDCA-treated PCK rats. (C and D) Hepatic expression of the cholangiocyte-marker Ck19 at protein level. Representative images of Ck19 immunohistochemistry (C) and western blots (D) of 5 representative untreated or UDCA-treated PCK rats. Bar graph shows Ck19 quantification (n=10 and n=9 in PCK and PCK+UDCA groups, respectively). (E) Representative images (Sirius Red staining; 5× magnification) and bar graph showing the hepatic collagen deposition in untreated and UDCA-treated PCK rats. (F) Expression levels (mRNA) of pro-fibrotic (Col1a1 and Ctgf) and pro-inflammatory (Cxcl1) genes in liver of wild-type and PCK (untreated and UDCA-treated) rats. (G) Open field test (distance and average speed) in untreated and UDCA-treated PCK rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups unless specified.
PCK rats show increased intrahepatic bile acid concentration compared to wild-type rats, and UDCA decreases the intrahepatic accumulation of cytotoxic bile acids in PCK rats. (A) Total bile acid concentration ([BA]) in liver of wild-type and PCK rats (untreated and UDCA-treated). (B) Levels of both primary (CA and CDCA) and secondary (DCA and LCA) major species of BAs in liver of wild-type and PCK (untreated and UDCA-treated) rats. (C) Intrahepatic levels of the toxic dihydroxylated BAs (TDCA, TCDCA, GDCA and GCDCA) in wild-type and PCK (untreated and UDCA-treated) rats. (D) Proportion of unconjugated and, tauro- and glyco-conjugated BAs in wild-type and PCK (untreated and UDCA-treated) rats. (E) Expression level (mRNA) of Cyp7a1 in liver of wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show increased intrahepatic bile acid concentration compared to wild-type rats, and UDCA decreases the intrahepatic accumulation of cytotoxic bile acids in PCK rats. (A) Total bile acid concentration ([BA]) in liver of wild-type and PCK rats (untreated and UDCA-treated). (B) Levels of both primary (CA and CDCA) and secondary (DCA and LCA) major species of BAs in liver of wild-type and PCK (untreated and UDCA-treated) rats. (C) Intrahepatic levels of the toxic dihydroxylated BAs (TDCA, TCDCA, GDCA and GCDCA) in wild-type and PCK (untreated and UDCA-treated) rats. (D) Proportion of unconjugated and, tauro- and glyco-conjugated BAs in wild-type and PCK (untreated and UDCA-treated) rats. (E) Expression level (mRNA) of Cyp7a1 in liver of wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show increased intrahepatic bile acid concentration compared to wild-type rats, and UDCA decreases the intrahepatic accumulation of cytotoxic bile acids in PCK rats. (A) Total bile acid concentration ([BA]) in liver of wild-type and PCK rats (untreated and UDCA-treated). (B) Levels of both primary (CA and CDCA) and secondary (DCA and LCA) major species of BAs in liver of wild-type and PCK (untreated and UDCA-treated) rats. (C) Intrahepatic levels of the toxic dihydroxylated BAs (TDCA, TCDCA, GDCA and GCDCA) in wild-type and PCK (untreated and UDCA-treated) rats. (D) Proportion of unconjugated and, tauro- and glyco-conjugated BAs in wild-type and PCK (untreated and UDCA-treated) rats. (E) Expression level (mRNA) of Cyp7a1 in liver of wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show increased intrahepatic bile acid concentration compared to wild-type rats, and UDCA decreases the intrahepatic accumulation of cytotoxic bile acids in PCK rats. (A) Total bile acid concentration ([BA]) in liver of wild-type and PCK rats (untreated and UDCA-treated). (B) Levels of both primary (CA and CDCA) and secondary (DCA and LCA) major species of BAs in liver of wild-type and PCK (untreated and UDCA-treated) rats. (C) Intrahepatic levels of the toxic dihydroxylated BAs (TDCA, TCDCA, GDCA and GCDCA) in wild-type and PCK (untreated and UDCA-treated) rats. (D) Proportion of unconjugated and, tauro- and glyco-conjugated BAs in wild-type and PCK (untreated and UDCA-treated) rats. (E) Expression level (mRNA) of Cyp7a1 in liver of wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show increased intrahepatic bile acid concentration compared to wild-type rats, and UDCA decreases the intrahepatic accumulation of cytotoxic bile acids in PCK rats. (A) Total bile acid concentration ([BA]) in liver of wild-type and PCK rats (untreated and UDCA-treated). (B) Levels of both primary (CA and CDCA) and secondary (DCA and LCA) major species of BAs in liver of wild-type and PCK (untreated and UDCA-treated) rats. (C) Intrahepatic levels of the toxic dihydroxylated BAs (TDCA, TCDCA, GDCA and GCDCA) in wild-type and PCK (untreated and UDCA-treated) rats. (D) Proportion of unconjugated and, tauro- and glyco-conjugated BAs in wild-type and PCK (untreated and UDCA-treated) rats. (E) Expression level (mRNA) of Cyp7a1 in liver of wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show decreased [BA] in bile, and UDCA normalizes it and increases the BA secretion to bile. (A,B) [BA] in bile of wild-type and PCK (untreated and UDCA-treated) rats. (A,C) BA secretion to bile in wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show decreased [BA] in bile, and UDCA normalizes it and increases the BA secretion to bile. (A,B) [BA] in bile of wild-type and PCK (untreated and UDCA-treated) rats. (A,C) BA secretion to bile in wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
PCK rats show decreased [BA] in bile, and UDCA normalizes it and increases the BA secretion to bile. (A,B) [BA] in bile of wild-type and PCK (untreated and UDCA-treated) rats. (A,C) BA secretion to bile in wild-type and PCK (untreated and UDCA-treated) rats. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
The cystic fluid of PLD patients presents increased [BA] compared to their matched serum levels. Dots represent each patient (n=11).
PCK rats show increased total [BA] in peripheral blood compared to wild-type rats, as well as decreased UDCA family levels that are upregulated by UDCA treatment. N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) rats.
The [BA] is increased in kidneys of PCK rats compared to wild-type rats and is diminished by UDCA treatment (A, B, C). N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
The [BA] is increased in kidneys of PCK rats compared to wild-type rats and is diminished by UDCA treatment (A, B, C). N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
The [BA] is increased in kidneys of PCK rats compared to wild-type rats and is diminished by UDCA treatment (A, B, C). N=12 in wild-type (untreated) and n=10 in PCK (untreated and UDCA-treated) groups.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
UDCA inhibits the proliferation of polycystic human cholangiocytes by raising the intracellular calcium levels and via a PI3K/AKT/MEK/ERK1/2-dependent mechanism. (A) Proliferation of normal and polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium. (B) Protein expression of the pro-mitotic marker PCNA in polycystic human cholangiocytes in the presence or absence of UDCA in the culture medium (C) Basal apoptotic rates in normal and polycystic human cholangiocytes in the presence or absence of UDCA. (D) Role of MEK in basal and UDCA-inhibited proliferation of polycystic human cholangiocytes. (E) Role of TUDCA in the basal proliferation of polycystic human cholangiocytes. (F) Representative experiment and bar graph showing the intracellular calcium levels in normal and polycystic human cholangiocytes (n=number of cell groups analyzed). (G, H) Representative western blots and bar graphs showing AKT (G) and ERK1/2 (H) phosphorylation levels in the presence or absence of UDCA and/or PI3K-inhibitor. (I) Role of GDCA, UDCA and TUDCA in the proliferation of proliferation of polycystic human cholangiocytes. (J) Working model: hepatic cystogenesis in PLDs is characterized by cAMP/PKA/MEK/ERK1/2-dependent cholangiocyte hyperproliferation associated to decreased intracellular calcium level. The [BA] is increased in the liver of PCK rats and may promote the proliferation of polycystic cholangiocytes. UDCA inhibits the MEK/ERK1/2-dependent proliferation of polycystic cholangiocytes via Ca2+/PI3K/AKT mechanism, resulting in decreased hepatic cystogenesis and fibrosis. UDCA, through its choleretic features, may also flow the increased concentration of cytotoxic bile acids in the liver preventing their biliary pathogenic effects.
Source: PubMed