Premium
Inhibition of hepatic phosphatidylcholine synthesis by AICAR and phenformin is independent of AMP‐activated protein kinase (AMPK) activation.
Author(s) -
Lingrell Susanne,
Jacobs René L,
Dyck Jason R.B.,
Vance Dennis E
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a91-b
Subject(s) - ampk , phenformin , chemistry , phosphatidylethanolamine , choline kinase , protein kinase a , phosphatidylcholine , choline , biochemistry , microbiology and biotechnology , kinase , phospholipid , endocrinology , metformin , biology , diabetes mellitus , membrane
Hepatocytes can synthesize phosphatidylcholine (PC) via two pathways; the CDP‐choline pathway, is expressed in all cells and requires dietary choline. In the second (liver‐specific) pathway, phosphatidylethanolamine is methylated to phosphatidylcholine via the enzyme phosphatidylethanolamine N‐methyltransferase (PEMT). The present study investigated whether AMPK regulates phosphatidylcholine biosynthesis in hepatocytes. Chemical activator of AMPK (phenformin and AICAR) inhibited both PC biosynthetic pathways in isolated hepatocytes, suggesting AMPK plays an important role in regulating phospholipid metabolism. However, when isolated hepatocytes were infected with a recombinant adenovirus expressing a constitutively active form of AMPK, there was no change in the rate of phosphatidycholine formation. Furthermore, adenovirus expression of a dominant‐negative mutant of AMPK did not block the effects of phenformin and AICAR. By measuring enzyme activities and pathway intermediates we were able to show that phenformin and AICAR have different sites of action. For example, phenformin directly inhibits in vitro PEMT activity while AICAR does not. It appears that AICAR may inhibit PEMT‐flux by increasing the intracellular concentration of S‐adenosylhomocysteine, a potent inhibitor of methylation reactions. AICAR seems to inhibit the CDP‐choline pathway by increasing choline oxidation while phenformin seems in impair choline uptake into the cell. Taken together, this study indicates that AICAR and phenformin are potent inhibitors of hepatic PC biosynthesis however these affects are independent of AMPK action.