Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.
Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARalpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARalpha activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARalpha in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.
Martin
G
G
Département d'Athérosclérose, UR 545 Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur de Lille and Faculté de Pharmacie, Universite de Lille II, Lille, France.
Duez
H
H
Blanquart
C
C
Berezowski
V
V
Poulain
P
P
Fruchart
J C
JC
Najib-Fruchart
J
J
Glineur
C
C
Staels
B
B
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016895:Culture Media, Serum-Free; D003497:Cyclic N-Oxides; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000096:biosynthesis / Q000378:metabolism; D008623:Mercaptoethanol / Q000031:analogs & derivatives; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D016895:Culture Media, Serum-Free; D003497:Cyclic N-Oxides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D011725:Pyridines; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D008623:Mercaptoethanol; C040255:SL-mercaptoethanol; C086276:cerivastatin; C006012:fenofibric acid; D006903:Hydroxymethylglutaryl CoA Reductases; D020741:rho GTP-Binding Proteins; C108475:pitavastatin; D011345:Fenofibrate