Hypoxia converts human macrophages into triglyceride-loaded foam cells.
OBJECTIVE
Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells.


RESULTS
Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in beta-oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl-coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of beta-oxidation, whereas the accumulation of triglycerides increased.


CONCLUSIONS
The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.
Boström
Pontus
P
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg, Sweden.
Magnusson
Björn
B
Svensson
Per-Arne
PA
Wiklund
Olov
O
Borén
Jan
J
Carlsson
Lena M S
LM
Ståhlman
Marcus
M
Olofsson
Sven-Olof
SO
Hultén
Lillemor Mattsson
LM
D042964:Acyl-CoA Dehydrogenase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D003600:Cytosol / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D015151:Immunoblotting; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000070780:Perilipin-2; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism*
D008077:Lipoproteins, LDL; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D012333:RNA, Messenger; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D013230:Stearoyl-CoA Desaturase; D042964:Acyl-CoA Dehydrogenase; D003066:Coenzyme A Ligases