Fibrillar collagen inhibits cholesterol biosynthesis in human aortic smooth muscle cells.
OBJECTIVE
Integrin-mediated cell adhesion to type I fibrillar collagen regulates gene and protein expression, whereas little is known of its effect on lipid metabolism. In the present study, we examined the effect of type I fibrillar collagen on cholesterol biosynthesis in human aortic smooth muscle cells (SMCs).


RESULTS
SMCs were cultured on either fibrillar or monomer collagen for 48 hours and [(14)C]-acetate incorporation into cholesterol was evaluated. Fibrillar collagen reduced by 72.9+/-2.6% cholesterol biosynthesis without affecting cellular cholesterol levels. Fibrillar collagen also reduced 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) promoter activity (-72.6+/-7.3%), mRNA (-58.7+/-6.4%), protein levels (-35.5+/-8.5%), and enzyme activity (-37.7+/-2.2%). Intracellular levels of the active form of sterol regulatory element binding proteins (SREBP) 1a was decreased by 60.7+/-21.7% in SMCs cultured on fibrillar collagen, whereas SREBP2 was not significantly affected (+12.1+/-7.1%). The overexpression of the active form of SREBP1a rescued the downregulation of fibrillar collagen on HMG-CoA reductase levels. Blocking antibody to alpha2 integrin partially reversed the downregulation of HMG-CoA reductase mRNA expression. Finally, fibrillar collagen led to an intracellular accumulation of unprenylated Ras.


CONCLUSIONS
Our study demonstrated that alpha2 beta 1 integrin interaction with fibrillar collagen affected the expression of HMG-CoA reductase, which led to the inhibition of cholesterol biosynthesis in human SMCs.
Ferri
Nicola
N
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milano, Italy. nicola.ferri@unimi.it
Roncalli
Elisa
E
Arnaboldi
Lorenzo
L
Fenu
Simone
S
Andrukhova
Olena
O
Aharinejad
Seyedhossein
S
Camera
Marina
M
Tremoli
Elena
E
Corsini
Alberto
A
D001013:Aorta, Thoracic / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D024022:Fibrillar Collagens / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000502:physiology; D038982:Integrin alpha2beta1 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017368:Protein Prenylation; D012333:RNA, Messenger / Q000032:analysis; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
D024022:Fibrillar Collagens; D038982:Integrin alpha2beta1; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D018631:ras Proteins