Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice.
OBJECTIVE
Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100-containing lipoproteins in cultured hepatocytes and improves the dyslipidemia and insulin resistance in a mouse model of the metabolic syndrome. In the present study, we used low-density lipoprotein receptor-null mice fed a high-fat diet (Western, TD96125) to test the hypothesis that naringenin prevents atherosclerosis.


RESULTS
Three groups (chow, Western, and Western plus naringenin) were fed ad libitum for 6 months. The Western diet increased fasting plasma triglyceride (TG) (5-fold) and cholesterol (8-fold) levels compared with chow, whereas the addition of naringenin significantly decreased both lipids by 50%. The Western-fed mice developed extensive atherosclerosis in the aortic sinus because plaque area was increased by 10-fold compared with chow-fed animals. Quantitation of fat-soluble dye (Sudan IV)-stained aortas, prepared en face, revealed that Western-fed mice also had a 10-fold increase in plaque deposits throughout the arch and in the abdominal sections of the aorta, compared with chow. Atherosclerosis in both areas was significantly decreased by more than 70% in naringenin-treated mice. Consistent with quantitation of aortic lesions, the Western-fed mice had a significant 6-fold increase in cholesterol and a 4-fold increase in TG deposition in the aorta compared with chow-fed mice. Both were reduced more than 50% by naringenin. The Western diet induced extensive hepatic steatosis, with a 10-fold increase in both TG and cholesteryl ester mass compared with chow. The addition of naringenin decreased both liver TG and cholesteryl ester mass by 80%. The hyperinsulinemia and obesity that developed in Western-fed mice was normalized by naringenin to levels observed in chow-fed mice.


CONCLUSIONS
These in vivo studies demonstrate that the citrus flavonoid naringenin ameliorates the dyslipidemia in Western-fed low-density lipoprotein receptor-null mice, leading to decreased atherosclerosis; and suggests a potential therapeutic strategy for the hyperlipidemia and increased risk of atherosclerosis associated with insulin resistance.
Mulvihill
Erin E
EE
Vascular Biology Group, Robarts Research Institute, The University of Western Ontario, 100 Perth Dr, London, ON, Canada.
Assini
Julia M
JM
Sutherland
Brian G
BG
DiMattia
Alessandra S
AS
Khami
Maryam
M
Koppes
Julie B
JB
Sawyez
Cynthia G
CG
Whitman
Stewart C
SC
Huff
Murray W
MW
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000378:metabolism; D004036:Diet, Atherogenic; D004041:Dietary Fats; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control; D044950:Flavanones / Q000494:pharmacology*; D006946:Hyperinsulinism / Q000209:etiology / Q000517:prevention & control; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D044950:Flavanones; D000960:Hypolipidemic Agents; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; C005273:naringenin