👤 Jordi Merino

To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication. High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat. BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets. Show less

To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). We used Bayesian network analyses to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with fatty liver using data from the IMI-DIRECT prospective cohort study. Measurements were made of glucose and insulin dynamics (using frequently-sampled metabolic challenge tests), MRI-derived abdominal and liver fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults free from diabetes at enrolment. The common protocols used in these two cohorts provided the opportunity for replication analyses to be performed. When the direction of the effect could not be determined with high probability through Bayesian networks, complementary two-sample Mendelian randomization (MR) was employed. High basal insulin secretion rate (BasalISR) was identified as the primary causal driver of liver fat accumulation in both diabetes and non-diabetes. Excess visceral adipose tissue (VAT) was bidirectionally associated with liver fat, indicating a self-reinforcing metabolic loop. Basal insulin clearance (Clinsb) worsened as a consequence of liver fat accumulation to a greater degree before the onset of T2D. Out of 446 analysed proteins, 34 mapped to these metabolic networks and 27 were identified in the non-diabetes network, 18 in the diabetes network, and 11 were common between the two networks. Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses revealed distinct proteomic drivers: GUSB and LEP were most predictive of liver fat in females and males, respectively. Basal insulin hypersecretion is a modifiable, causal driver of MASLD, particularly prior to glycaemic decompensation. Our findings highlight a multifactorial, sex- and disease-stage-specific proteo-metabolic architecture of hepatic steatosis. Proteins such as GUSB, ALDH1A1, LPL, and IGFBPs warrant further investigation as potential biomarkers or therapeutic targets for MASLD prevention and treatment. Show less

The Coastal Creole pigs in Argentina are predominantly found in the wild and can trace their lineage directly back to the Iberian breeds introduced by Spanish colonizers. They currently stand as the sole Creole breed in the country recognized by the FAO. However, there exists a dearth of studies assessing their genetic potential within the swine industry. Therefore, this study aimed to genetically characterize the meat quality of Coastal Creole pigs based on seven single nucleotide polymorphisms (SNPs) within the Ryr1, PRKAG3, MC4R, H-FABP, and CAST genes. A total of N = 158 samples were collected from specimens distributed along the coastal region. Our findings revealed all loci to exhibit polymorphism, underscoring the population's remarkable genetic diversity. Furthermore, a higher frequency of alleles favorable for the PRKAG3 Show less

Diabetic macular oedema (DMO) is a complication of diabetic retinopathy that can result in vision loss. The disease can impact different spheres of a patient's life, including physical and psychological health, work, and activities of daily living, entailing an important use of healthcare and non-healthcare resources. This study aimed to estimate the socio-economic burden of DMO in Spain. The burden of DMO was estimated from a societal perspective, per patient, year of treatment since diagnosis, and type of treatment. Four categories were considered: direct healthcare costs (DHC), direct non-healthcare costs (DNHC), labour productivity losses (LPL), and intangible costs (IC) associated with loss of quality of life. Average annual costs were calculated by multiplying the resources used per patient by their corresponding unit price (or financial proxy). For a more accurate estimation, differences in resource use between treatments (intravitreal anti-vascular endothelial growth factor injections of ranibizumab or aflibercept, and intravitreal dexamethasone implants) and year since diagnosis (first, second, and third year or beyond) were considered and presented separately. The reference year for costs was 2021. The average annual costs of DMO in the first year of treatment after diagnosis was estimated at €18,774, €17,512, and €16,188 per patient treated with ranibizumab, aflibercept, and dexamethasone, respectively. This burden would be reduced to €15,783, €15,701, and €12,233 in the second year, and to €15,119, €15,043, and €12,790 in the third year, respectively. Diagnosis of DMO entails an additional one-off cost of €485. DHC accounted for the greatest proportion of total annual costs per patient, independent of the year, with LPL also making an important contribution to total costs. The socio-economic impact of DMO on patients, the healthcare system, and society at large is substantial. The constant increase in its prevalence accentuates the need for planning and implementation of healthcare strategies to prevent vision loss and reduce the socio-economic burden of the disease. Show less

Neovascular age-related macular degeneration (nAMD) is a progressive retinal disease that causes severe and irreversible vision loss. The disease can therefore have a significant impact on the life of patients' and their families. The aim of this study was to evaluate the socio-economic burden of nAMD in Spain. The annual cost per patient with nAMD was estimated for the first, second, and third year (or beyond) of treatment since diagnosis. Several cost categories were considered including direct healthcare costs (DHC), direct non-healthcare costs (DNHC), labor productivity losses (LPL), and intangible costs (IC) related to loss of quality of life. The average annual cost per patient was estimated by assigning a unit price or financial proxy to the resources consumed per patient. Reference year of costs was 2021. The mean annual cost of nAMD was estimated at €17,265, €15,403, and €14,465 per patient in the first, second, and third year of treatment after diagnosis. There was an additional one-off cost of €744 associated with the diagnosis of nAMD. DHC accounted for most of the total annual cost per patient independent of the year of treatment since diagnosis (48% in year 1; 42% in year 2; 39% in year 3). Similarly, DNHC had an important contribution to the total costs (32% in year 1; 35% in year 2; 37% in year 3), followed by IC (20% in year 1; 23% in year 2; 24% in year 3), while the contribution of patients' LPL was minimal. This study estimated a high economic burden associated with nAMD for patients and their families, the healthcare system, and society at large. There is a need to improve the management of these patients to reduce the impact of nAMD disease progression. Show less

Urokinase-type plasminogen activator (uPA) is a serine proteinase found in excitatory synapses located in the II/III and V cortical layers. The synaptic release of uPA promotes the formation of synaptic contacts and the repair of synapses damaged by various forms of injury, and its abundance is decreased in the synapse of Alzheimer's disease (AD) patients. Inactivation of the Wingless/Int1 (Wnt)-β-catenin pathway plays a central role in the pathogenesis of AD. Soluble amyloid-β (Aβ) prevents the phosphorylation of the low-density lipoprotein receptor-related protein-6 (LRP6), and the resultant inactivation of the Wnt-β-catenin pathway prompts the amyloidogenic processing of the amyloid-β protein precursor (AβPP) and causes synaptic loss. To study the role of neuronal uPA in the pathogenesis of AD. We used in vitro cultures of murine cerebral cortical neurons, a murine neuroblastoma cell line transfected with the APP-695 Swedish mutation (N2asw), and mice deficient on either plasminogen, or uPA, or its receptor (uPAR). We show that uPA activates the Wnt-β-catenin pathway in cerebral cortical neurons by triggering the phosphorylation of LRP6 via a plasmin-independent mechanism that does not require binding of Wnt ligands (Wnts). Our data indicate that uPA-induced activation of the Wnt-β-catenin pathway protects the synapse from the harmful effects of soluble Aβ and prevents the amyloidogenic processing of AβPP by inhibiting the expression of β-secretase 1 (BACE1) and the ensuing generation of Aβ40 and Aβ42 peptides. uPA protects the synapse and antagonizes the inhibitory effect of soluble Aβ on the Wnt-β-catenin pathway by providing an alternative pathway for LRP6 phosphorylation and β-catenin stabilization. Show less

Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases. Show less

ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; Our results identified genetic variants in the Show less

Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn Show less

The incorporation of plasma triglyceride (TG) fatty acids to white adipose tissue (WAT) depends on lipoprotein lipase (LPL), which is regulated by angiopoietin-like protein-4 (ANGPTL-4), an unfolding molecular chaperone that converts active LPL dimers into inactive monomers. The production of ANGPTL-4 is promoted by fasting and repressed by feeding. We hypothesized that the postprandial hormone cholecystokinin (CCK) facilitates the storage of dietary TG fatty acids in WAT by regulating the activity of the LPL/ANGPTL-4 axis and that it does so by acting directly on CCK receptors in adipocytes. We report that administration of CCK-8 (a bioactive fragment of CCK) to rats: (i) reduces plasma ANGTPL-4 levels; (ii) represses Show less

Recent evidence indicates that genetic variation in fatty acid desaturases 1 and 2 (FADS1 and FADS2) is associated with changes in plasma fatty acid profiles; however, the association with altered desaturase activity has not been examined in different ethnic populations. The present study examined whether genetic variation in the FADS gene cluster regulates desaturase activity in two populations of young Canadian adults (Caucasian and Asian) and whether altered desaturase activity was reflected in both n-3 and n-6 fatty acid profiles. FADS1 and FADS2 were genotyped in a random subset of participants (Caucasian, n=78; Asian, n=69) from the Toronto Nutrigenomics and Health study using MALDI-TOF mass spectrometry, and plasma fatty acids were measured by gas chromatography. Desaturase activities were estimated using the following fatty acid ratios: γ-linoleic acid to linoleic acid (GLA:LA), arachidonic acid to linoleic acid (AA:LA), arachidonic acid to dihomo-γ-linoleic acid (AA:DGLA), and eicosapentaneoic acid to α-linolenic acid (EPA:ALA). Nineteen single nucleotide polymorphisms (SNPs) were examined, and several SNPs (9 in Caucasians and 8 in Asians) were associated with various desaturase activities. The most significant association detected was between the FADS1 rs174547 SNP and AA:LA in both Caucasians (p=4.0 × 10(-8)) and Asians (p=5.0 × 10(-5)). Although the minor allele for this SNP differed between Caucasians (T) and Asians (C), carriers of the C allele had a lower desaturase activity than carriers of the T allele in both groups. To determine whether rs174547 was a dominant SNP in the FADS gene cluster, we constructed an additional model which included this SNP as a covariate. Only one SNP (rs498793 in FADS2) remained associated with the EPA:ALA ratio (p=1.1 × 10(-5)) in Asians. This study shows that genetic variation in the FADS gene cluster (in particular rs174547) can alter desaturase activity in subjects of Caucasians and Asian descent. Show less

Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management. Show less