Resveratrol-Induced Changes in MicroRNA Expression in Primary Human Fibroblasts Harboring Carnitine-Palmitoyl Transferase-2 Gene Mutation, Leading to Fatty Acid Oxidation Deficiency

Abstract

Carnitine palmitoyltransferase-2 (CPT2) is a mitochondrial enzyme involved in long-chain fatty acid entry into mitochondria for their β-oxidation and energy production. Two phenotypes are associated with the extremely reduced CPT2 activity in genetically deficient patients: neonatal lethality or, in milder forms, myopathy. Resveratrol (RSV) is a phytophenol produced by grape plant in response to biotic or abiotic stresses that displays anti-oxidant properties, in particular through AP-1, NFκB, STAT-3, and COX pathways. Some beneficiary effects of RSV are due to its modulation of microRNA (miRNA) expression. RSV can enhance residual CPT2 activities in human fibroblasts derived from CPT2-deficient patients and restores normal fatty acid oxidation rates likely through stimulation of mitochondrial biogenesis. Here, we report changes in miRNA expression linked to CPT2-deficiency, and we identify miRNAs whose expression changed following RSV treatment of control or CPT2-deficient fibroblasts isolated from patients. Our findings suggest that RSV consumption might exert beneficiary effects in patients with CPT2-deficiency.

Resveratrol-Dependent Stimulation of Mitochondrial Fatty Acid Oxidation in Deficient Cells. Implication of miRNAs

“…While we previously identified RSV-dependent miRNA modulation in THP-1 macrophages [3], here we report changes in miRNA expression linked to CPT2-deficiency. We also identified miRNAs whose expression changed following RSV treatment of control or CPT2-deficient fibroblasts isolated from patients [4]. We found that miR-378 was down-regulated by RSV in control fibroblasts.…”

Quercetin, Epigallocatechin Gallate, Curcumin, and Resveratrol: From Dietary Sources to Human MicroRNA Modulation

“…In primary human fibroblasts, resveratrol was able decrease miR-566 and miR-23a, restoring mitochondrial fatty acid β-oxidation rates in primary human fibroblasts form patients harboring carnitine palmitoyltransferase-2 mutation associated with two different phenotypes (neonatal lethality or myopathy in mild forms) [120]. Therefore, resveratrol, independently of the disease, led to miR-566 and miR-23a modulation specifically [120]. Microarray analysis showed that human THP-1 monocytic cells treated with resveratrol increased the expression of miR-663 decreasing miR-155 [121].…”

Structure, Chemical Analysis, Biosynthesis, Metabolism, Molecular Engineering, and Biological Functions of Phytoalexins

“…These compounds have been the subject of numerous studies over the last two decades. Thirteen research and review articles have been published in this special issue: four articles concern the biosynthesis of phytoalexins as a response to biotic and/or abiotic elicitors capable of inducing their production in plants [ 1 , 2 , 3 , 4 ], two articles describe methods for phytoalexin analysis in complex matrices [ 5 , 6 ], one article reports on phytoalexin metabolism by fungi [ 7 ], and six articles focus on the biological activity of phytoalexins [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

“…Beside their antifungal properties in plants, phytoalexins show preventing activities against human diseases as antioxidant, anticancer, cardioprotective, antibacterial, and antifungal agents. Six articles report here on the biological implication of phytoalexins in human diseases [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

“…It thus seems that labruscol possesses complementary properties of resveratrol in particular regarding cell invasion, suggesting its utilization in combination with resveratrol to improve its antiproliferative capacities. In the work of Aires et al [ 12 ], the identification of microRNAs was described following treatment of human primary fibroblasts with resveratrol. This study focuses on the relation between resveratrol treatment and deficiency in Carnitine-Palmitoyl Transferase-2 (CTP2), a mitochondrial enzyme involved in long-chain fatty acids entry into the mitochondria for their β-oxidation and energy production.…”