PPARdelta is a very low-density lipoprotein sensor in macrophages.
Although triglyceride-rich particles, such as very low-density lipoprotein (VLDL), contribute significantly to human atherogenesis, the molecular basis for lipoprotein-driven pathogenicity is poorly understood. We demonstrate that in macrophages, VLDL functions as a transcriptional regulator via the activation of the nuclear receptor peroxisome proliferator-activated receptor delta. The signaling components of native VLDL are its triglycerides, whose activity is enhanced by lipoprotein lipase. Generation of peroxisome proliferator-activated receptor delta null macrophages verifies the absolute requirement of this transcription factor in mediating the VLDL response. Thus, our data reveal a pathway through which dietary triglycerides and VLDL can directly regulate gene expression in atherosclerotic lesions.
Chawla
Ajay
A
The Salk Institute for Biological Studies, Howard Hughes Medical Institute, La Jolla, CA 90237, USA.
Lee
Chih-Hao
CH
Barak
Yaacov
Y
He
Weimin
W
Rosenfeld
John
J
Liao
Debbie
D
Han
Jungyeob
J
Kang
Heonjoong
H
Evans
Ronald M
RM
D016475:3T3 Cells; D000483:Alleles; D000818:Animals; D015152:Blotting, Northern; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D017930:Genes, Reporter; D005822:Genetic Vectors; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D010100:Oxygen / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D008079:Lipoproteins, VLDL; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D010100:Oxygen