Selective regulation of UGT1A1 and SREBP‐1c mRNA expression by docosahexaenoic, eicosapentaenoic, and arachidonic acids

Abstract

We evaluated, in human cell line HepG2, the action of individual dietary polyunsaturated fatty acids (PUFAs) on the expression of several lipid metabolism genes. The effects of docosahexaenoic acid, 22:6, n-3 (DHA), eicosapentaenoic acid, 20:5, n-3 (EPA), and arachidonic acid, 20:4, n-6 (AA) were studied alone and with vitamin E (Vit.E). DHA, EPA, and AA down-regulated mRNAs and encoded proteins of stearoyl-CoA desaturase (SCD) and sterol regulatory element binding protein (SREBP-1c), two major factors involved in unsaturated fatty acids synthesis. DHA affected SREBP-1c mRNA less markedly than EPA and AA. Vit.E did not affect these products, both when individually added or together with fatty acids. The expression of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA, an enzyme of phase II drug metabolism with relevant actions within lipid metabolism, resulted also differentially regulated. DHA did not essentially reduce UGT1A1 mRNA expression while EPA and AA produced a considerable decrease. Nevertheless, when these PUFAs were combined with Vit.E, which by itself did not produce any effect, the result was a reduction of UGT1A1 mRNA with DHA, an increase reverting to basal level with EPA and no variation with AA. Observed regulations did not result to be mediated by peroxisome proliferator-activated receptor (PPAR). Our data indicate that major dietary PUFAs and Vit.E are differentially and selectively able to affect the expression of genes involved in lipid metabolism. The different actions of these slightly different molecules could be associated with their physiological role as relevant nutrient molecules.

Selective action of human sera differing in fatty acids and cholesterol content on in vitro gene expression

“…Our data show that hypercholesterolemic sera are able to reduce mRNA expression of this lipid-related transcription factor. This finding is in agreement with our previous data where individual pure fatty acids such as DHA, EPA, and AA directly administered on the same liver cell culture induced a down regulation of SREBP-1c [Caputo et al, 2011]. Our data in Figure 3 show that higher levels of AA and LA correspond to elevated gene expression of UGT1A1.…”

“…Other data show that UGT1A1 induction by pro-inflammatory molecules (such as AA and LA) might represent a key adaptive response to cellular oxidative stress that defends against a variety of detrimental stimuli [Yueh and Tukey, 2007], as in our condition, for example, UGT1A1 expression could be influenced by hypercholesterolemic serum samples. The additional role of inflammatory factors, present in these sera within hypercholesterolemic status, could explain the different result of our previous data in which individual fatty acids reduced UGT1A1 mRNA [Caputo et al, 2011].…”

Effect of dietary eicosapentaenoic and docosahexaenoic acid on expression of rat liver genes controlling cholesterol homeostasis and on plasma cholesterol level

“…Regarding SREBP, Caputo et al (2010), using PPARα antagonist, argued that an effect of EPA/DHA on SREBP-1c expression is not mediated through PPARα action. On the other hand, Fernandez-Alvarez et al (2011) reported that PPAR/RXR heterodimer activated SREBP-1c promoter and a PPARα agonist increased SREBP-1c expression in the rat liver.…”

“…Lu et al (2011) found a decrease of an amount of both the precursor and the nuclear SREBP-1 protein in their experiment. It is worthy to mention in this context an effect of concentration: Caputo et al (2010) reported a decrease of both SREBP-1 mRNA and SREBP-1 protein in human hepatoma treated with EPA/DHA, but only in concentration of 50μM and not in concentration of 25μM.…”

Nutrigenómica: Revelando Los Aspectos Moleculares De Una Nutrición Personalizada

“…Se ha observado que el ácido docosahexaenoico (22:6 n-3, DHA) y el ácido eicosapentaenoico (20:5 n-3, EPA) ejercen su acción a través de la interacción con receptores del tipo PPAR, HNF-4, LXR, RXR y SREBP 1c, con lo cual generan respuestas reguladoras (35). El DHA está estrechamente relacionado con la protección del sistema nervioso ya que a través de la activación del PPAR-γ disminuye la producción de…”