Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.
Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) alpha but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein (SREBP)-1. We have previously shown that the disruption of SREBP-1 in ob/ob mice decreased their liver triglyceride storage. To examine whether PUFAs could reduce hepatic triglyceride deposition, we challenged ob/ob mice with dietary PUFA. It is demonstrated that PUFA markedly decreased the mature form of SREBP-1 protein and thereby reduced the expression of lipogenic genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in the livers of ob/ob mice. Consequently, the liver triglyceride content and plasma alanine aminotransferase (ALT) levels were decreased. Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPARalpha activators. In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha.
Sekiya
Motohiro
M
Department of Internal Medicine, Tokyo University Graduate School of Medicine, Tokyo, Japan.
Yahagi
Naoya
N
Matsuzaka
Takashi
T
Najima
Yuho
Y
Nakakuki
Masanori
M
Nagai
Ryozo
R
Ishibashi
Shun
S
Osuga
Jun-ichi
J
Yamada
Nobuhiro
N
Shimano
Hitoshi
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D005234:Fatty Liver / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D007333:Insulin Resistance; D008099:Liver / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000502:physiology; D014280:Triglycerides / Q000032:analysis
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D000410:Alanine Transaminase