Plasma membrane form of phosphatidate phosphohydrolase: a possible role in signal transduction during liver fibrogenesis.
1. Several growth factors important in liver regeneration and fibrosis stimulate phospholipase D in plasma membranes via a receptor/G-protein-coupled mechanism resulting in hydrolysis of phosphatidylcholine to phosphatidate. Phosphatidate can be further hydrolysed to diacylglycerol by phosphatidate phosphohydrolase. Phosphatidate and diacylglycerol can act as 'second-messengers' and regulation of phosphatidate phosphohydrolase activity could control the balance between them. 2. A form of phosphatidate phosphohydrolase, located in the plasma membrane and insensitive to inhibition by N-ethylmaleimide, has recently been identified that is distinct from the 'metabolic' form, which is present in the cytosol and microsomes and is sensitive to N-ethylmaleimide. 3. We have investigated the hypothesis that the balance between regeneration and fibrosis is, in part, determined by the activity of plasma membrane phosphatidate phosphohydrolase through its effect on the phosphatidate/diacylglycerol ratio. N-Ethylmaleimide-insensitive and -sensitive phosphatidate phosphohydrolase activities were measured in three hepatic conditions characterized by regeneration and/or fibrosis: alcoholic liver disease in humans (regeneration and fibrosis) and rat livers after either acute CCl-4-induced injury (regeneration) or common bile duct ligation (fibrosis). 4. In patients with alcoholic liver disease, N-ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was higher in cirrhotic biopsies (5.82 +/- 0.3 nmol of Pi min-1 mg-1 of protein, n = 19) than in non-cirrhotic biopsies (2.17 +/- 0.2, n = 23) or in wedge biopsies from healthy subjects undergoing routine cholecystectomy (2.16 +/- 0.5, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)
Day
C P
CP
Department of Biochemistry and Genetics, Medical School, University of Newcastle, U.K.
Burt
A D
AD
Brown
A S
AS
Bennett
M K
MK
Farrell
D J
DJ
James
O F
OF
Yeaman
S J
SJ
D000818:Animals; D002251:Carbon Tetrachloride; D002462:Cell Membrane / Q000201:enzymology; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000209:etiology; D005355:Fibrosis / Q000139:chemically induced; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology* / Q000209:etiology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology; D008115:Liver Regeneration / Q000502:physiology; D010711:Phosphatidate Phosphatase / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
D002251:Carbon Tetrachloride; D010711:Phosphatidate Phosphatase