title: Activation of AMP-kinase by policosanol requires peroxisomal metabolism.
abstract: Policosanol, a well-defined mixture of very long chain primary alcohols that is available as a nutraceutical product, has been reported to lower blood cholesterol levels. The present studies demonstrate that policosanol promotes the phosphorylation of AMP-kinase and HMG-CoA reductase in hepatoma cells and in mouse liver after intragastric administration, providing a possible means by which policosanol might lower blood cholesterol levels. Treatment of hepatoma cells with policosanol produced a 2.5-fold or greater increase in the phosphorylation of AMP-kinase and HMG-CoA reductase, and increased the phosphorylation of Ca(++)/calmodulin-dependent kinase kinase (CaMKK), an upstream AMP-kinase kinase. Intragastric administration of policosanol to mice similarly increased the phosphorylation of hepatic HMG-CoA reductase and AMP-kinase by greater than 2-fold. siRNA-mediated suppression of fatty aldehyde dehydrogenase, fatty acyl-CoA synthetase 4, and acyl-CoA acetyltransferase expression in hepatoma cells prevented the phosphorylation of AMP-kinase and HMG-CoA reductase by policosanol, indicating that metabolism of these very long chain alcohols to activated fatty acids is necessary for the suppression of cholesterol synthesis, presumably by increasing cellular AMP levels. Subsequent peroxisomal β-oxidation probably augments this effect.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA.
authors.forename: Subhashis
authors.initials: S
authors.lastname: Banerjee
authors.forename: Sarbani
authors.initials: S
authors.lastname: Ghoshal
authors.forename: Todd D
authors.initials: TD
authors.lastname: Porter
mesh_terms: D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism*; D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D005233:Fatty Alcohols / Q000378:metabolism*; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008687:Metformin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020675:Peroxisomes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D005233:Fatty Alcohols; D007004:Hypoglycemic Agents; D012265:Ribonucleotides; C080710:policosanol; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D006903:Hydroxymethylglutaryl CoA Reductases; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide