👤 Josep M Folch

The intramuscular oleic-to-stearic fatty acid ratio (C18:1n-9/C18:0) is an important indicator of the biosynthesis and desaturation of fatty acids in muscle. By using an RNA-Seq approach in muscle samples from 32 BC1_DU (25% Iberian and 75% Duroc) pigs with divergent values (high: H and low: L) of C18:1n-9/C18:0 fatty acids ratio, a total of 81 differentially expressed genes (DEGs) were identified. Functional analyses of DEGs indicate that mainly peroxisome proliferator-activated receptor signaling pathway (associated genes: PPARG, SCD, PLIN1, and FABP3) was overrepresented. Notably, SCD is directly involved in the conversion of C18:0 to C18:1n-9, and PPARG is a transcription factor regulating lipid metabolism genes, including SCD. However, other DEGs (e.g., ACADVL, FADS3, EPHB2, HGFAC, NGFR, NR0B2, MDH1, MMAA, PPP1R1B, SFRP5, RAB30, and TRARG1) are plausible candidate genes to explain the phenotypic differences of the C18:1n-9/C18:0 ratio. Interestingly, seven genetic variants within the SCD (including the well-known AY487830:g.2228T>C SNP and other novel genotyped polymorphisms) are associated with two haplotypes. Although the haplotypes are segregating at different frequencies in the H and L groups, they do not fully explain the desaturation ratios or the SCD expression levels. A more complex model, including polyunsaturated fatty acids such as C18:2n-6, C20:4n-6, and C18:3n-3, is suggested to explain the regulation of the C18:1n-9/C18:0 desaturation ratio in porcine muscle. Show less

The composition and distribution of fatty acids (FA) are important factors determining the quality, flavor, and nutrient value of meat. In addition, FAs synthesized in the body participate in energy metabolism and are involved in different regulatory pathways in the form of signaling molecules or by acting as agonist or antagonist ligands of different nuclear receptors. Finally, synthesis and catabolism of FAs affect adaptive immunity by regulating lymphocyte metabolism. The present study performed genome-wide association studies using FA profiles of blood, liver, backfat and muscle from 432 commercial Duroc pigs. Twenty-five genomic regions located on 15 Sus scrofa chromosomes (SSC) were detected. Annotation of the quantitative trait locus (QTL) regions identified 49 lipid metabolism-related candidate genes. Among these QTLs, four were identified in more than one tissue. The ratio of C20:4n-6/C20:3n-6 was associated with the region on SSC2 at 7.56-14.26 Mb for backfat, liver, and muscle. Members of the fatty acid desaturase gene cluster (FADS1, FADS2, and FADS3) are the most promising candidate genes in this region. Two QTL regions on SSC14 (103.81-115.64 Mb and 100.91-128.14 Mb) were identified for FA desaturation in backfat and muscle. In addition, two separate regions on SSC9 at 0 - 14.55 Mb and on SSC12 at 0-1.91 Mb were both associated with the same multiple FA traits for backfat, with candidate genes involved in de novo FA synthesis and triacylglycerol (TAG) metabolism, such as DGAT2 and FASN. The ratio C20:0/C18:0 was associated with the region on SSC5 at 64.84-78.32 Mb for backfat. Furthermore, the association of the C16:0 content with the region at 118.92-123.95 Mb on SSC4 was blood specific. Finally, candidate genes involved in de novo lipogenesis regulate T cell differentiation and promote the generation of palmitoleate, an adipokine that alleviates inflammation. Several SNPs and candidate genes were associated with lipid metabolism in blood, liver, backfat, and muscle. These results contribute to elucidating the molecular mechanisms implicated in the determination of the FA profile in different pig tissues and can be useful in selection programs that aim to improve health and energy metabolism in pigs. Show less

Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, β-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition. Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aβ Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease. Show less

The intramuscular fat content and fatty acid composition of porcine meat have a significant impact on its quality and nutritional value. This research aimed to investigate the expression of 45 genes involved in lipid metabolism in the longissimus dorsi muscle of three experimental pig backcrosses, with a 25% of Iberian background. To achieve this objective, we conducted an expression Genome-Wide Association Study (eGWAS) using gene expression levels in muscle measured by high-throughput real-time qPCR for 45 target genes and genotypes from the PorcineSNP60 BeadChip or Axiom Porcine Genotyping Array and 65 single nucleotide polymorphisms (SNPs) located in 20 genes genotyped by a custom-designed Taqman OpenArray in a cohort of 354 animals. The eGWAS analysis identified 301 eSNPs associated with 18 candidate genes (ANK2, APOE, ARNT, CIITA, CPT1A, EGF, ELOVL6, ELOVL7, FADS3, FASN, GPAT3, NR1D2, NR1H2, PLIN1, PPAP2A, RORA, RXRA and UCP3). Three cis-eQTL (expression quantitative trait loci) were identified for GPAT3, RXRA, and UCP3 genes, which indicates that a genetic polymorphism proximal to the same gene is affecting its expression. Furthermore, 24 trans-eQTLs were detected, and eight candidate regulatory genes were located in these genomic regions. Additionally, two trans-regulatory hotspots in Sus scrofa chromosomes 13 and 15 were identified. Moreover, a co-expression analysis performed on 89 candidate genes and the fatty acid composition revealed the regulatory role of four genes (FABP5, PPARG, SCD, and SREBF1). These genes modulate the levels of α-linolenic, arachidonic, and oleic acids, as well as regulating the expression of other candidate genes associated with lipid metabolism. The findings of this study offer novel insights into the functional regulatory mechanism of genes involved in lipid metabolism, thereby enhancing our understanding of this complex biological process. Show less

We conducted a cross-sectional study in a Spanish population (n = 1,029) to investigate associations between the LPL and APOC3 gene loci (LPL-HindIII, LPL-S447X, and APOC3-SstI) and plasma lipid levels and their interaction with APOE polymorphisms and smoking. Carriers of the H(-) or the X447 allele had higher levels of HDL cholesterol (HDL-C), and lower levels of TG, after adjustment for age, body mass index, alcohol, smoking, exercise, and education (P < 0.01). The APOC3 polymorphism presented additive effects to the LPL variants on TG and HDL-C levels in men, and on TG in women. The most and the least favorable haplotype combinations were H(-)/X447/S1 and H(+)/S447/S2, respectively. These combinations accounted for 7% and 5% of the variation in HDL-C and TG in men, and 3% and 4% in women. There was a significant interaction between APOE and LPL variants and HDL-C levels in both genders (P < 0.05). The increases in HDL-C observed for the rare alleles were higher in epsilon4 than in epsilon3 subjects, and absent in epsilon2 individuals. This effect was modulated by smoking (interaction HindIII-APOE-smoking, P = 0.019), indicating that smoking abolished the increase in HDL-C levels observed in epsilon4/H(-) subjects. Understanding this gene-gene-environmental interaction may facilitate preventive interventions to reduce coronary artery disease risk. Show less