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Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP‐activated protein kinase
Author(s) -
Henin Nathalie,
Vincent M.Françoise,
Gruber Harry E.,
Van Den Berghe Georges
Publication year - 1995
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.9.7.7737463
Subject(s) - pyruvate carboxylase , biochemistry , protein kinase a , fatty acid synthesis , acetyl coa carboxylase , pyruvate kinase , chemistry , enzyme , pkm2 , amp activated protein kinase , biology , glycolysis , ampk
AMP‐activated protein kinase is a multisubstrate protein kinase that, in liver, inactivates both acetyl‐CoA carboxylase, the rate‐limiting enzyme of fatty acid synthesis, and 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase, the rate‐limiting enzyme of cholesterol synthesis. AICAR (5‐amino 4‐imidazolecarboxamide ribotide, ZMP) was found to stimulate up to 10‐fold rat liver AMP‐activated protein kinase, with a half‐maximal effect at approximately 5 mM. In accordance with previous observations, addition to suspensions of isolated rat hepatocytes of 50–500 μM AICAriboside, the nucleoside corresponding to ZMP, resulted in the accumulation of millimolar concentrations of the latter. This was accompanied by a dose‐dependent inactivation of both acetyl‐CoA carboxylase and 3‐hydroxy‐3‐methylglutaryl‐CoA reductase. Addition of 50–500 μM AICAriboside to hepatocyte suspensions incubated in the presence of various substrates, including glucose and lactate/pyruvate, caused a parallel inhibition of both fatty acid and cholesterol synthesis. With lactate/pyruvate (10/1 mM), half‐maximal inhibition was obtained at approximately 100 μM, and near‐complete inhibition at 500 μM AI‐CAriboside. These findings open new perspectives for the simultaneous control of triglyceride and cholesterol synthesis by pharmacological stimulators of AMP‐activated protein kinase.—Henin, N., Vincent, M.‐F., Gruber, H. E., Van den Berghe, G. Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP‐activated protein kinase. FASEB J. 9, 541–546 (1995)