Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mRNAs.
Dietary fish oil induces hepatic peroxisomal and microsomal fatty acid oxidation by peroxisome proliferator-activator receptor alpha activation, whereas it down-regulates lipogenic gene expression by unknown mechanism(s). Because sterol regulatory element-binding proteins (SREBPs) up-regulated lipogenic genes, investigation was made on the effects of fish oil feeding on SREBPs and sterol regulatory element (SRE)-dependent gene expression in C57BL/6J mice. Three forms of SREBPs, SREBP-1a, -1c, and -2, are expressed in liver, and their truncated mature forms activate transcription of sterol-regulated genes. C57BL/6J mice were divided into three groups; the first group was given a high carbohydrate diet, and the other two groups were given a high fat diet (60% of total energy), with the fat in the form of safflower oil or fish oil, for 5 months. Compared with safflower oil feeding, fish oil feeding decreased triglyceride and cholesterol concentrations in liver. There were no differences in amount of SREBP-1 and -2 in both precursor and mature forms between carbohydrate- and safflower oil-fed mice. However, compared with safflower oil feeding, fish oil feeding reduced the amounts of precursor SREBP-1 in membrane fraction by 90% and of mature SREBP-1 in liver nuclei by 57%. Fish oil feeding also reduced precursor SREBP-2 by 65% but did not alter the amount of mature SREBP-2. Compared with safflower oil feeding, fish oil feeding decreased liver SREBP-1c mRNA level by 86% but did not alter SERBP-1a mRNA. Consistent with decrease of mature SREBP-1, compared with safflower oil feeding, fish oil feeding down-regulated the expression of liver SRE-dependent genes, such as low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA synthase, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1. These data suggested that in liver, fish oil feeding down-regulates the mature form of SREBP-1 by decreasing SREBP-1c mRNA expression, with corresponding decreases of mRNAs of cholesterologenic and lipogenic enzymes.
Kim
H J
HJ
Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan.
Takahashi
M
M
Ezaki
O
O
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004032:Diet; D015536:Down-Regulation; D005260:Female; D005395:Fish Oils / Q000008:administration & dosage*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014413:Tuna
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005395:Fish Oils; D009687:Nuclear Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors