Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

International audiencePrevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole-body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte-specific glucose-6-phosphatase deficient (L-G6pc-/- ) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L-G6pc-/- mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very-low-density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L-G6pc-/- mice, and further elevated in hypoglycemic L-G6pc-/- mice. VLDL-TG secretion rates were doubled in normo- and hypoglycemic L-G6pc-/- mice, while VLDL-TG catabolism was selectively inhibited in hypoglycemic L-G6pc-/- mice. In conclusion, fasting-induced hypoglycemia in L-G6pc-/- mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients

Walk to me when I smile, step back when I’m angry: emotional faces modulate whole-body approach–avoidance behaviors

Facial expressions are potent social cues that can induce behavioral dispositions, such as approach–avoidance tendencies. We studied these tendencies by asking participants to make whole-body forward (approach) or backward (avoidance) steps on a force plate in response to the valence of social cues (happy or angry faces) under affect-congruent and incongruent mappings. Posturographic parameters of the steps related to automatic stimulus evaluation, step initiation (reaction time), and step execution were determined and analyzed as a function of stimulus valence and stimulus–response mapping. The main result was that participants needed more time to initiate a forward step towards an angry face than towards a smiling face (which is evidence of a congruency effect), but with backward steps, this difference failed to reach significance. We also found a reduction in spontaneous body sway prior to the step with the incongruent mapping. The results provide a crucial empirical link between theories of socially induced action tendencies and theories of postural control and suggest a motoric basis for socially guided motivated behavior

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg-0.22, P =5.5x10-13), T2D (rg-0.27, P =1.1x10-6) and coronary artery disease (rg-0.30, P =6.5x10-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P =1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust

Molecular characterization of organic matter in converted forests in Western Europe; disentangling the effects of edaphic factors and input differences on SOM composition

status: publishe

Disentangling the effects of parent material and litter input chemistry on molecular soil organic matter composition in converted forests in Western Europe

By storing carbon in the soil, forests contribute to climate change mitigation. Edaphic (soil-related) factors, such as soil pH, as well as tree species affect forest carbon cycles, but are difficult to disentangle. We studied how conversion of deciduous stands to mono-culture spruce plantations affected the soil organic matter (SOM) composition along a lithological gradient in the Mullerthal (Luxembourg) and Gaume (south-east Belgium) regions. Parent materials in these regions range from decalcified sands to calcareous marls. A twin plot setup of adjacent deciduous and coniferous stands on the same parent material was used to evaluate the effect of edaphic factors versus litter input differences on SOM composition and soil organic carbon (SOC) stocks. Lignin and cutin/suberin molecular proxies were identified with thermally assisted hydrolysis and methylation (THM), to distinguish litter sources (coniferous vs deciduous and leaf litter vs roots) in the studied stands. In this study, SOC stocks were influenced more by parent material than by forest type. Lignin yield, composition and degradation state were influenced both by litter input chemistry and edaphic context. There appear to be important interaction effects between the two, as the relative importance of parent material and litter quality was site specific. We therefore advice that carbon stock models include data on both vegetation history as well as edaphic context.status: publishe

Disentangling the effects of parent material and litter input chemistry on molecular soil organic matter composition in converted forests in Western Europe

By storing carbon in the soil, forests contribute to climate change mitigation. Edaphic (soil-related) factors, such as soil pH, as well as tree species affect forest carbon cycles, but are difficult to disentangle. We studied how conversion of deciduous stands to mono-culture spruce plantations affected the soil organic matter (SOM) composition along a lithological gradient in the Mullerthal (Luxembourg) and Gaume (south-east Belgium) regions. Parent materials in these regions range from decalcified sands to calcareous marls. A twin plot setup of adjacent deciduous and coniferous stands on the same parent material was used to evaluate the effect of edaphic factors versus litter input differences on SOM composition and soil organic carbon (SOC) stocks. Lignin and cutin/suberin molecular proxies were identified with thermally assisted hydrolysis and methylation (THM), to distinguish litter sources (coniferous vs deciduous and leaf litter vs roots) in the studied stands. In this study, SOC stocks were influenced more by parent material than by forest type. Lignin yield, composition and degradation state were influenced both by litter input chemistry and edaphic context. There appear to be important interaction effects between the two, as the relative importance of parent material and litter quality was site specific. We therefore advice that carbon stock models include data on both vegetation history as well as edaphic context

Organic matter in converted forest soils inWestern Europe: disentangling the effects of edaphic factors and input differences on its composition

status: publishe

What Makes the Bioactive Lipids Phosphatidic Acid and Lysophosphatidic Acid So Special? †

ABSTRACT: Phosphatidic acid and lysophosphatidic acid are minor but important anionic bioactive lipids involved in a number of key cellular processes, yet these molecules have a simple phosphate headgroup. To find out what is so special about these lipids, we determined the ionization behavior of phosphatidic acid (PA) and lysophosphatidic acid (LPA) in extended (flat) mixed lipid bilayers using magic angle spinning 31 P NMR. Our data show two surprising results. First, despite identical phosphomonoester headgroups, LPA carries more negative charge than PA when present in a phosphatidylcholine bilayer. Dehydroxy-LPA [1-oleoyl-3-(phosphoryl)propanediol] behaves in a manner identical to that of PA, indicating that the difference in negative charge between LPA and PA is caused by the hydroxyl on the glycerol backbone of LPA and its interaction with the phosphomonoester headgroup. Second, deprotonation of phosphatidic acid and lysophosphatidic acid was found to be strongly stimulated by the inclusion of phosphatidylethanolamine in the bilayer, indicating that lipid headgroup charge depends on local lipid composition and will vary between the different subcellular locations of (L)PA. Our findings can be understood in terms of a hydrogen bond formed within the phosphomonoester headgroup of (L)PA and its destabilization by competing intra- or intermolecular hydrogen bonds. We propose that this hydrogen bonding property of (L)PA is involved in the various cellular functions of these lipids