Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S]
Functional defects in ATPase class I type 8B membrane 1 (ATP8B1 or familial intrahepatic cholestasis 1, FIC1) lead to cholestasis by mechanism(s) that are not fully understood. One proposed pathophysiology involves aberrant signaling to the bile acid sensor, the farnesoid X receptor (FXR), via prote...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-02-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520428032 |
| _version_ | 1831772095263014912 |
|---|---|
| author | Frank Chen Ayantika Ghosh Benjamin L. Shneider |
| author_facet | Frank Chen Ayantika Ghosh Benjamin L. Shneider |
| author_sort | Frank Chen |
| collection | DOAJ |
| description | Functional defects in ATPase class I type 8B membrane 1 (ATP8B1 or familial intrahepatic cholestasis 1, FIC1) lead to cholestasis by mechanism(s) that are not fully understood. One proposed pathophysiology involves aberrant signaling to the bile acid sensor, the farnesoid X receptor (FXR), via protein kinase C ζ (PKCζ). The following cell line-based studies investigated whether phospholipase D2 may transduce a signal from FIC1 to FXR. PLD2 gain of function led to activation of the bile salt export pump (BSEP) promoter, a well-characterized FXR response. BSEP activation by PLD2 could be blocked by abrogating either PKCζ or FXR signaling. PLD2 loss of function led to a reduction in BSEP promoter activity. In addition, a variety of proteins that are activated by FXR, including BSEP, were reduced in HepG2 cells treated with PLD2 siRNA. Similar effects were observed in freshly isolated human hepatocytes. Activation of BSEP by FIC1 gain of function was blocked when PLD2 but not PLD1 was silenced. Overexpression of wild-type but not Byler mutant FIC1 led to an increase in membrane associated PLD activity. An intermediate level of activation of PLD activity was induced when a benign recurrent intrahepatic cholestasis FIC1 mutant construct was expressed. These studies show that FIC1 signals to FXR via a signaling pathway including PLD2 and PKCζ. |
| first_indexed | 2024-12-22T08:11:18Z |
| format | Article |
| id | doaj.art-48a41c3d36dd4292b3f224695fb9a2df |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-22T08:11:18Z |
| publishDate | 2013-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-48a41c3d36dd4292b3f224695fb9a2df2022-12-21T18:33:00ZengElsevierJournal of Lipid Research0022-22752013-02-01542379385Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S]Frank Chen0Ayantika Ghosh1Benjamin L. Shneider2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PADivision of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PATo whom correspondence should be addressed Benjamin.Shneider@chp.edu; To whom correspondence should be addressed Benjamin.Shneider@chp.edu; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PAFunctional defects in ATPase class I type 8B membrane 1 (ATP8B1 or familial intrahepatic cholestasis 1, FIC1) lead to cholestasis by mechanism(s) that are not fully understood. One proposed pathophysiology involves aberrant signaling to the bile acid sensor, the farnesoid X receptor (FXR), via protein kinase C ζ (PKCζ). The following cell line-based studies investigated whether phospholipase D2 may transduce a signal from FIC1 to FXR. PLD2 gain of function led to activation of the bile salt export pump (BSEP) promoter, a well-characterized FXR response. BSEP activation by PLD2 could be blocked by abrogating either PKCζ or FXR signaling. PLD2 loss of function led to a reduction in BSEP promoter activity. In addition, a variety of proteins that are activated by FXR, including BSEP, were reduced in HepG2 cells treated with PLD2 siRNA. Similar effects were observed in freshly isolated human hepatocytes. Activation of BSEP by FIC1 gain of function was blocked when PLD2 but not PLD1 was silenced. Overexpression of wild-type but not Byler mutant FIC1 led to an increase in membrane associated PLD activity. An intermediate level of activation of PLD activity was induced when a benign recurrent intrahepatic cholestasis FIC1 mutant construct was expressed. These studies show that FIC1 signals to FXR via a signaling pathway including PLD2 and PKCζ.http://www.sciencedirect.com/science/article/pii/S0022227520428032bilecholestasisintestineileumlipidphoshatidic acid |
| spellingShingle | Frank Chen Ayantika Ghosh Benjamin L. Shneider Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S] Journal of Lipid Research bile cholestasis intestine ileum lipid phoshatidic acid |
| title | Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S] |
| title_full | Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S] |
| title_fullStr | Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S] |
| title_full_unstemmed | Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S] |
| title_short | Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S] |
| title_sort | phospholipase d2 mediates signaling by atpase class i type 8b membrane 1 s |
| topic | bile cholestasis intestine ileum lipid phoshatidic acid |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520428032 |
| work_keys_str_mv | AT frankchen phospholipased2mediatessignalingbyatpaseclassitype8bmembrane1s AT ayantikaghosh phospholipased2mediatessignalingbyatpaseclassitype8bmembrane1s AT benjaminlshneider phospholipased2mediatessignalingbyatpaseclassitype8bmembrane1s |