Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice.
Although the anti-inflammatory effect of interleukin-1 (IL-1) receptor antagonist (IL-1Ra) has been described, the contribution of this cytokine to cholesterol metabolism remains unclear. Our aim was to ascertain whether deficiency of IL-1Ra deteriorates cholesterol metabolism upon consumption of an atherogenic diet. IL-1Ra-deficient mice (IL-1Ra(-/-)) showed severe fatty liver and portal fibrosis containing many inflammatory cells following 20 weeks of an atherogenic diet when compared with wild type (WT) mice. Expectedly, the levels of total cholesterol in IL-1Ra(-/-) mice were significantly increased, and the start of lipid accumulation in liver was observed earlier when compared with WT mice. Real-time PCR analysis revealed that IL-1Ra(-/-) mice failed to induce mRNA expression of cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, with concurrent up-regulation of small heterodimer partner 1 mRNA expression. Indeed, IL-1Ra(-/-) mice showed markedly decreased bile acid excretion, which is elevated in WT mice to maintain cholesterol level under atherogenic diet feeding. Therefore, we conclude that the lack of IL-1Ra deteriorates cholesterol homeostasis under atherogenic diet-induced inflammation.
Isoda
Kikuo
K
Internal Medicine I, National Defense Medical College, Tokorozawa 359-8513, Japan. isoda@me.ndmc.ac.jp
Sawada
Shojiro
S
Ayaori
Makoto
M
Matsuki
Taizo
T
Horai
Reiko
R
Kagata
Yutaka
Y
Miyazaki
Koji
K
Kusuhara
Masatoshi
M
Okazaki
Mitsuyo
M
Matsubara
Osamu
O
Iwakura
Yoichiro
Y
Ohsuzu
Fumitaka
F
D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics; D004036:Diet, Atherogenic; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000209:etiology*; D007249:Inflammation / Q000209:etiology; D053590:Interleukin 1 Receptor Antagonist Protein; D008103:Liver Cirrhosis / Q000209:etiology; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012795:Sialoglycoproteins / Q000172:deficiency*
D001647:Bile Acids and Salts; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012795:Sialoglycoproteins; C099713:nuclear receptor subfamily 0, group B, member 2; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase