AMPK activation by long chain fatty acyl analogs

作者：Za'tara Ghadeer; Bar Tana Jacob; Kalderon Bella; Suter Marianne; Morad Etedal; Samovski Dmitry; Neumann Dietbert; Hertz Rachel^*

来源：Biochemical Pharmacology, 2008, 76(10): 1263-1275.

DOI：10.1016/j.bcp.2008.08.028

• AMPK
• Diabetes
• MEDICA
• Fatty acids
• Acyl-CoA

The antidiabetic efficacy of first-line insulin sensitizers (e.g., metformin, glitazones) is accounted for by activation of AMP-activated protein kinase (AMPK). Long chain fatty acids (LCFA) activate AMPK, but their putative antidiabetic efficacy is masked by their p-oxidized or esterified lipid products. Substituted alpha,beta-dicarboxylic acids of 14-18 carbon atoms in length (MEDICA analogs) are not metabolized beyond their acyl-CoA thioesters, and may therefore simulate AMPK activation by LCFA while avoiding LCFA turnover into P-oxidized or esterified lipid products. MEDICA analogs are shown here to activate AMPK and some of its downstream targets in vivo, in cultured cells and in a cell-free system consisting of the (alpha(1)beta(1)gamma(1))AMPK recombinant and LKB1-MO25-STRAD (AMPK-kinase) recombinant proteins. AMPK activation by MEDICA is accompanied by normalizing the hyperglycemia-hyperinsulinemia of diabetic db/db mice in vivo with suppression of hepatic glucose production in cultured liver cells. Activation of AMPK by MEDICA or LCFA is accounted for by (a) decreased intracellular ATP/AMP ratio and energy charge by the free acid, (b) activation of LKB1 phosphorylation of AMPK(Thr172) by the acyl-CoA thioester. The two activation modes are complementary since LKB1/AMPK activation by the CoA-thioester is fully evident under conditions of excess AMP. MEDICA analogs may expand the arsenal of AMPK activators used for treating diabetes type 2.

• 出版日期2008-11-15