👤 Lilia G Noriega

An increased number of low-density lipoprotein particles (LDL-P) is a common feature of patients with Metabolic syndrome (MetS). Increasing the size of these particles is one of the primary therapeutic and dietary interventions goals. However, genetic variability, like single nucleotide polymorphisms (SNPs), modulate the response to dietary strategies. Therefore, we hypothesise that the presence of SNPs in genes associated with MetS may modulate the effect of a dietary intervention on the size of LDL-P. This was a before-and-after clinical study conducted with 146 participants with MetS. The participants underwent a lifestyle intervention for 10 weeks. At baseline the presence of SNPs associated with MetS were determined. Anthropometric, biochemical, hormonal parameters, and lipoprotein analysis were taken before and after the intervention. Results revealed that the common homozygous ATP-binding cassette transporter A1 (ABCA1) genotype was associated with a decreased LDL-C concentration. However, after adjusting for sex, age and baseline weight, polymorphisms in the fat mass and obesity-associated (FTO) gene, the peroxisome proliferator-activated receptor (PPARγ), and the apolipoprotein E (APOE) gene were associated with a better response to the intervention in terms of increasing LDL-P size. Our results revealed changes in LDL-P size associated with polymorphisms in the APOE, FTO and PPARγ genes in response to the dietary intervention. These results highlight the importance of genetic factors in personalized nutritional strategies aimed at improving cardiovascular risk in patients with MetS. NCT03611140, www. gov. Show less

Childhood obesity increases the risk of developing metabolic diseases in adulthood, since environmental stimuli during critical windows of development can impact on adult metabolic health. Studies demonstrating the effect of prepubertal diet on adult metabolic disease risk are still limited. We hypothesized that a prepubertal control diet (CD) protects the adult metabolic phenotype from diet-induced obesity (DIO), while a high-fat diet (HFD) would predispose to adult metabolic alterations. Sprague-Dawley male rats were fed either a CD or a HFD during the prepubertal period (day 30-40 of age) and subsequently a chronic HFD or CD, respectively, until adulthood (day 220 of age). As controls, rats aged 30 days were exclusively fed a CD or a HFD until adulthood. Body weight and composition, metabolic rate, biochemical and hormonal plasma measurements, hepatic gene expression and methylation and hydroxymethylation levels were analyzed at ages 30, 40 and 220 days. The prepubertal CD prevented fat mass accumulation, lean mass loss and metabolic inflexibility, showed lower insulin, leptin and cholesterol concentrations in adulthood despite the chronic HFD. Notably, the prepubertal CD led to higher hepatic Lxrα expression, lower hepatic global DNA methylation and higher hydroxymethylation in adulthood despite a chronic HFD. Conversely, a prepubertal HFD decreased adult metabolic flexibility, increased serum cholesterol, and decreased Lxrα expression and global DNA hydroxymethylation, while also increasing DNA methylation levels despite a chronic CD. In summary, a prepubertal CD protected the adult metabolic phenotype from high cholesterol concentrations associated with increased hepatic Lxrα expression and lower hepatic global DNA methylation in adulthood, despite exposure to a chronic HFD. Conversely, a prepubertal HFD altered the adult metabolic phenotype. Show less

Carbohydrate responsive element-binding protein (ChREBP) has been identified as a primary transcription factor that maintains energy homeostasis through transcriptional regulation of glycolytic, lipogenic, and gluconeogenic enzymes in response to a high-carbohydrate diet. Amino acids are important substrates for gluconeogenesis, but nevertheless, knowledge is lacking about whether this transcription factor regulates genes involved in the transport or use of these metabolites. Here, we demonstrate that ChREBP represses the expression of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) in response to a high-sucrose diet in rats by binding to a carbohydrate response element (ChoRE) site located -160 bp upstream of the transcriptional start site in the SNAT2 promoter region. Additionally, immunoprecipitation assays revealed that ChREBP and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) interact with each other, as part of the complex that repress SNAT2 expression. The interaction between these proteins was confirmed by an in vivo chromatin immunoprecipitation assay. These findings suggest that glucogenic amino acid uptake by the liver is controlled by ChREBP through the repression of SNAT2 expression in rats consuming a high-carbohydrate diet. Show less

The nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1 is a major metabolic regulator activated by energy stresses such as fasting or calorie restriction. SIRT1 activation during fasting not only relies on the increase in the NAD(+)/NADH ratio caused by energy deprivation but also involves an upregulation of SIRT1 mRNA and protein levels in various metabolic tissues. We demonstrate that SIRT1 expression is controlled systemically by the activation of the cyclic AMP response-element-binding protein upon low nutrient availability. Conversely, in the absence of energetic stress, the carbohydrate response-element-binding protein represses the expression of SIRT1. Altogether, these results demonstrate that SIRT1 expression is tightly controlled at the transcriptional level by nutrient availability and further underscore that SIRT1 is a crucial metabolic checkpoint connecting the energetic status with transcriptional programmes. Show less