Centeno-Cruz, F. | bioRxiv Science

bioRxiv2021

Mct11 deficiency alters hepatic glucose metabolism and energy homeostasis

Genetic variation at the SLC16A11 locus contributes to the disproportionate impact of type 2 diabetes (T2D) on Latino populations. We recently demonstrated that T2D risk variants reduce SLC16A11 liver expression and function of MCT11, the monocarboxylate transporter encoded by the SLC16A11 gene. Here, we show that SLC16A11 expression within the liver is primarily localized to the low oxygen pericentral region, and that T2D risk variants disrupt oxygen-regulated SLC16A11 expression in human hepatocytes. Under physiologic oxygen conditions, MCT11 deficiency alters hepatocyte glucose metabolism, resulting in elevated intracellular lactate and a metabolic shift toward triacylglycerol accumulation. We also demonstrate an impact of Mct11 deficiency on glucose and lipid metabolism in Slc16a11 knockout mice, which display physiological changes that are observed in individuals with T2D. Our findings provide mechanistic insight into how SLC16A11 disruption impacts hepatic energy metabolism and T2D risk, and highlight MCT11-mediated regulation of lactate levels as a potential therapeutic target.

genetics↗

bioRxiv2020

Rare coding variants in 35 genes associate with circulating lipid levels: a multi-ancestry analysis of 170,000 exomes

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency<1%) predicted damaging coding variation using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

genetics↗