title: Metformin reduces cellular lysophosphatidylcholine and thereby may lower apolipoprotein B secretion in primary human hepatocytes.
abstract: The biguanide metformin is an oral antihyperglycemic drug for the treatment of type 2 diabetes mellitus. Further, a moderate improvement of dyslipidemia by metformin was reported, and therefore, the effect of metformin on the release of apolipoprotein B (ApoB) and ApoE in primary human hepatocytes was determined. Metformin at 0.5 and 1 mM reduced hepatic ApoB secretion but ApoE was not altered. Metformin is well known to stimulate the AMP kinase that subsequently reduces hepatic nuclear factor 4-alpha (HNF4-alpha) and HNF4-alpha regulated genes like ApoB. However, HNF4-alpha was only diminished by 1 mM metformin and ApoB mRNA was not suppressed indicating that this pathway may not explain reduced ApoB release. Lower abundance of lysophosphatidylcholine (lysoPC) may also diminish ApoB secretion. Therefore, electrospray ionization tandem mass spectrometry was applied to measure cellular lipids. PC, lysoPC (produced by hydrolysis of PC), phosphatidylserine and sphingomyelin (derived from PC) were lower in metformin-treated hepatocytes whereas phosphatidylethanolamine, an alternative precursor of PC, was not affected. In addition, ABCB4, the canalicular membrane flippase essential for biliary PC secretion, was diminished. Supplementation with lysoPC led to a selective elevation of endogenous lysoPC and rescued ApoB secretion in metformin-treated cells. Therefore, it is concluded that metformin reduces lysoPC in human hepatocytes and this may secondarily lead to a therapeutically beneficial lower release of ApoB.
authors.affiliation: Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Wanninger
authors.forename: Markus
authors.initials: M
authors.lastname: Neumeier
authors.forename: Johanna
authors.initials: J
authors.lastname: Weigert
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffler
authors.forename: Charalampos
authors.initials: C
authors.lastname: Aslanidis
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Christa
authors.initials: C
authors.lastname: Buechler
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D003470:Culture Media; D004591:Electrophoresis, Polyacrylamide Gel; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D001055:Apolipoproteins B; D003470:Culture Media; D007004:Hypoglycemic Agents; D008244:Lysophosphatidylcholines; D008687:Metformin