Alpha linolenic acid suppresses cholesterol and triacylglycerol biosynthesis pathway by suppressing SREBP2, SREBP1a and 1c expression.
Alpha linolenic acid suppresses cholesterol and triacylglycerol biosynthesis pathway by suppressing SREBP2, SREBP1a and 1c expression.
Year: 2013
Authors: Fukumitsu, S. Villareal, M.O. Onaga, S. Aida, K. Han, J. Isoda, H.
Publication Name: Cytotechnology
Publication Details: DOI 10.1007/s10616-012-9510-x
Abstract:
Alpha linolenic acid (ALA), a major fatty acid in flaxseed oil, has multiple functionalities such as anti cardiovascular and anti hypertensive activities. In this study, we investigated the effects of ALA on lipid metabolism and studied the possible mechanisms of its action in differentiated 3T3L1 adipocytes using DNA microarray analysis. From a total of 34,325 genes in the DNA chip, 87 genes were down regulated and 185 genes were up regulated at least twofold in differentiated 3T3L1 adipocyte cells treated with 300 lM ALA for a week, 5 to12 days after induction of cell differentiation, compared to ALA untreated 3T3L1 adipocytes (control). From the Reactome analysis results, eight lipid metabolism related genes involved in cholesterol and triacylglycerol biosynthesis pathway and lipid transport were significantly down regulated by ALA treatment. Furthermore, ALA significantly decreased the mRNA expressions of sterol regulatory element binding protein (SREBP)2, SREBP1a, SREBP1c and fatty acid synthase (FAS) in 3T3L1 adipocyte cells. On the other hand, the average levels of the gene expressions of carnitine palmitoyltransferase 1a (CPT1a) and leptin in 300 lM ALA treatment were increased by 1.7 and 2.9 fold, respectively, followed by an increase in the intracellular ATP content. These results show that ALA is likely to inhibit cholesterol and fatty acid biosynthesis pathway by suppressing the expression of transcriptional factor SREBPs. Furthermore, ALA promotes fatty acid oxidation in 3T3L1 adipocytes, thereby increasing its health benefits. (Authors abstract)
Metabolic syndrome is strongly associated with cholesterol and fatty acids biosynthesis controlled by a common family of transcription factors designated SREBP1a, 1c and 2. Previous reports have shown that administration of flaxseed lignan to mice significantly reduced high fat diet induced visceral and liver fat accumulation, blood total cholesterol and triacylglycerol.
Lignan also suppressed SREBP1c mRNA level and its target gene, FAS mRNA. The n3 PUFAs have been well studied for their effect on the regulation of gene expression. The molecular mechanism and genome-wide information using DNA microarray analysis of the effect of ALA on 3T3L1 adipocytes has not yet been investigated. The purpose of this study is to reveal the lipid metabolism related effects of ALA, specifically on cholesterol and triacylglycerol biosynthesis and fatty acid oxidation, and to elucidate the molecular mechanisms of the inhibitory effects of ALA treatment on 3T3L1 adipocyte cells based on DNA microarray and real time PCR data. Treatment with ALA resulted in lipid size reduction. DNA microarray analysis showed a down regulation in the gene expressions of metabolism related genes after ALA treatment.
ALA affected and suppressed genes that are involved in the following pathways: cholesterol biosynthesis, triacylglycerol biosynthesis and lipid transport. Further treatment with ALA in differentiated 3T3L1 adipocytes caused a down-regulation of the gene expression of the genes involved in cholesterol and triacylglycerol biosynthesis pathways. SREBP1a, SREBP2, SREB1c and FAS mRNA levels in the 300 lM ALA treated 3T3L1 adipocytes were significantly decreased. Cpt1a and leptin are lipid metabolism related enzymes and fatty acid oxidation related enzymes genes. In this study, the average mRNA expression levels of CPT1a and leptin in the 300 lM ALA-treated adipocytes were increased by 1.7-fold and 2.9-fold, respectively.
In conclusion, this study indicates ALA may be beneficial for the improvement of lipid metabolism by specifically targeting cholesterol, triacylglycerol biosynthesis and fatty acid oxidation in differentiated 3T3L1 adipocytes. This data suggests that regular consumption of 300 lM ALA (approximately 0.5 g/day as flaxseed oil) may help in improving overall health. (Editors abstract)
