title: Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice.
abstract: OBJECTIVE
  Consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherogenesis. Fatty acid binding proteins (FABP-4/aP2) and CD36 expression are key factors in lipid accumulation in macrophages and foam cell formation in atherogenesis. Our earlier observations suggest that curcumin's suppression of atherogenesis might be mediated through changes in aP2 and CD36 expression in macrophages. Thus, this study aimed to further elucidate the impact of increasing doses of curcumin on modulation of these molecular mediators on high fat diet-induced atherogenesis, inflammation, and steatohepatosis in Ldlr(-/-) mice.
  
  
  METHODS
  Ldlr(-/-) mice were fed low fat (LF) or high fat (HF) diet supplemented with curcumin (500 HF + LC; 1000 HF + MC; 1500 HF + HC mg/kg diet) for 16 wks. Fecal samples were analyzed for total lipid content. Lipids accumulation in THP-1 cells and expression of aP2, CD36 and lipid accumulation in peritoneal macrophages were measured. Fatty streak lesions and expression of IL-6 and MCP-1 in descending aortas were quantified. Aortic root was stained for fatty and fibrotic deposits and for the expression of aP2 and VCAM-1. Total free fatty acids, insulin, glucose, triglycerides, and cholesterol as well as several inflammatory cytokines were measured in plasma. The liver's total lipids, cholesterol, triglycerides, and HDL content were measured, and the presence of fat droplets, peri-portal fibrosis and glycogen was examined histologically.
  
  
  RESULTS
  Curcumin dose-dependently reduced uptake of oxLDL in THP-1 cells. Curcumin also reduced body weight gain and body fat without affecting fat distribution. During early intervention, curcumin decreased fecal fat, but at later stages, it increased fat excretion. Curcumin at medium doses of 500-1000 mg/kg diet was effective at reducing fatty streak formation and suppressing aortic expression of IL-6 in the descending aorta and blood levels of several inflammatory cytokines, but at a higher dose (HF + HC, 1500 mg/kg diet), it had adverse effects on some of these parameters. This U-shape like trend was also present when aortic root sections were examined histologically. However, at a high dose, curcumin suppressed development of steatohepatosis, reduced fibrotic tissue, and preserved glycogen levels in liver.
  
  
  CONCLUSIONS
  Curcumin through a series of complex mechanisms, alleviated the adverse effects of high fat diet on weight gain, fatty liver development, dyslipidemia, expression of inflammatory cytokines and atherosclerosis in Ldlr(-/-) mouse model of human atherosclerosis. One of the mechanisms by which low dose curcumin modulates atherogenesis is through suppression of aP2 and CD36 expression in macrophages, which are the key players in atherogenesis. Overall, these effects of curcumin are dose-dependent; specifically, a medium dose of curcumin in HF diet appears to be more effective than a higher dose of curcumin.
authors.affiliation: Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Hasan
authors.affiliation: Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA.
authors.forename: J-M
authors.initials: JM
authors.lastname: Zingg
authors.affiliation: Department of Pathology, Tufts School of Medicine, 145 Harrison Ave, Boston, MA 02111, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kwan
authors.affiliation: Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA.
authors.forename: T
authors.initials: T
authors.lastname: Noble
authors.affiliation: Comparative Biology Unit, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA.
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.affiliation: Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA. Electronic address: Mohsen.meydani@tufts.edu.
authors.forename: M
authors.initials: M
authors.lastname: Meydani
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001835:Body Weight; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003474:Curcumin / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000737:chemistry; D011973:Receptors, LDL / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D016207:Cytokines; D050556:Fatty Acid-Binding Proteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D003474:Curcumin; D010100:Oxygen
keywords: Atherosclerosis; Body weight; CD36; Curcumin; FABP-4/aP2; Fatty liver; Ldlr(−/−); Mice