ORCID Profile
0000-0002-9253-5816
Current Organisation
University of Helsinki
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Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.CEB.2017.12.007
Abstract: Animals regulate their physiology with respect to nutrient status, which requires nutrient sensing pathways. Simple carbohydrates, sugars, are sensed by the basic-helix-loop-helix leucine zipper transcription factors ChREBP/Mondo, together with their heterodimerization partner Mlx, which are well-established activators of sugar-induced lipogenesis. Loss of ChREBP/Mondo-Mlx in mouse and Drosophila leads to sugar intolerance, that is, inability to survive on sugar containing diet. Recent evidence has revealed that ChREBP/Mondo-Mlx responds to sugar and fatty acid-derived metabolites through several mechanisms and cross-connects with other nutrient sensing pathways. ChREBP/Mondo-Mlx controls several downstream transcription factors and hormones, which mediate not only readjustment of metabolic pathways, but also control feeding behavior, intestinal digestion, and circadian rhythm.
Publisher: eLife Sciences Publications, Ltd
Date: 27-11-2018
DOI: 10.7554/ELIFE.40841
Abstract: How dietary selection affects genome evolution to define the optimal range of nutrient intake is a poorly understood question with medical relevance. We have addressed this question by analyzing Drosophila simulans and sechellia, recently erged species with differential diet choice. D. sechellia larvae, specialized to a nutrient scarce diet, did not survive on sugar-rich conditions, while the generalist species D. simulans was sugar tolerant. Sugar tolerance in D. simulans was a tradeoff for performance on low-energy diet and was associated with global reprogramming of metabolic gene expression. Hybridization and phenotype-based introgression revealed the genomic regions of D. simulans that were sufficient for sugar tolerance. These regions included genes that are involved in mitochondrial ribosome biogenesis and intracellular signaling, such as PPP1R15/Gadd34 and SERCA, which contributed to sugar tolerance. In conclusion, genomic variation affecting genes involved in global metabolic control defines the optimal range for dietary macronutrient composition.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.SEMCDB.2012.02.007
Abstract: The paralogous transcription factors ChREBP and MondoA, together with their common binding partner Mlx, have emerged as key mediators of intracellular glucose sensing. By regulating target genes involved in glycolysis and lipogenesis, they mediate metabolic adaptation to changing glucose levels. As disturbed glucose homeostasis plays a central role in human metabolic diseases and as cancer cells often display altered glucose metabolism, better understanding of cellular glucose sensing will likely uncover new therapeutic opportunities. Here we review the regulation, function and evolutionary conservation of the ChREBP/MondoA-Mlx glucose sensing system and discuss possible directions for future research.
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2023
Publisher: Public Library of Science (PLoS)
Date: 04-04-2013
Publisher: Elsevier BV
Date: 06-2014
Publisher: EMBO
Date: 27-04-2015
Publisher: Public Library of Science (PLoS)
Date: 11-10-2021
DOI: 10.1371/JOURNAL.PGEN.1009855
Abstract: Nutrient-dependent gene regulation critically contributes to homeostatic control of animal physiology in changing nutrient landscape. In Drosophila , dietary sugars activate transcription factors (TFs), such as Mondo-Mlx, Sugarbabe and Cabut, which control metabolic gene expression to mediate physiological adaptation to high sugar diet. TFs that correspondingly control sugar responsive metabolic genes under conditions of low dietary sugar remain, however, poorly understood. Here we identify a role for Drosophila GATA TF Grain in metabolic gene regulation under both low and high sugar conditions. De novo motif prediction uncovered a significant over-representation of GATA-like motifs on the promoters of sugar-activated genes in Drosophila larvae, which are regulated by Grain, the fly ortholog of GATA1/2/3 subfamily. grain expression is activated by sugar in Mondo-Mlx-dependent manner and it contributes to sugar-responsive gene expression in the fat body. On the other hand, grain displays strong constitutive expression in the anterior midgut, where it drives lipogenic gene expression also under low sugar conditions. Consistently with these differential tissue-specific roles, Grain deficient larvae display delayed development on high sugar diet, while showing deregulated central carbon and lipid metabolism primarily on low sugar diet. Collectively, our study provides evidence for the role of a metazoan GATA transcription factor in nutrient-responsive metabolic gene regulation in vivo .
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.CELREP.2015.08.081
Abstract: The ChREBP/Mondo-Mlx transcription factors are activated by sugars and are essential for sugar tolerance. They promote the conversion of sugars to lipids, but beyond this, their physiological roles are insufficiently understood. Here, we demonstrate that in an organism-wide setting in Drosophila, Mondo-Mlx controls the majority of sugar-regulated genes involved in nutrient digestion and transport as well as carbohydrate, amino acid, and lipid metabolism. Furthermore, human orthologs of the Mondo-Mlx targets display enrichment among gene variants associated with high circulating triglycerides. In addition to direct regulation of metabolic genes, Mondo-Mlx maintains metabolic homeostasis through downstream effectors, including the Activin ligand Dawdle and the Gli-similar transcription factor Sugarbabe. Sugarbabe controls a subset of Mondo-Mlx-dependent processes, including de novo lipogenesis and fatty acid desaturation. In sum, Mondo-Mlx is a master regulator of other sugar-responsive pathways essential for adaptation to a high-sugar diet.
Publisher: Bioscientifica
Date: 09-2010
DOI: 10.1677/ERC-10-0041
Abstract: Disturbances in granulosa cell apoptosis have been implicated in the pathogenesis of human granulosa cell tumors (GCTs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cytokine that induces apoptosis in a variety of malignancies without toxic effects on benign cells. The aim of this study was to investigate the expression and functionality of the TRAIL receptors DR4 and DR5 in human GCTs. Additionally, we examined the role of GATA4, a transcription factor expressed in normal and malignant granulosa cells, in TRAIL-induced GCT apoptosis. For this purpose, a tissue microarray of 80 primary and 12 recurrent GCTs was subjected to immunohistochemistry for DR4 and DR5, and freshly isolated primary GCT cultures were utilized to evaluate the functional effects of TRAIL on GCT cells. To clarify the role of GATA4 in the regulation of TRAIL-induced apoptosis, a human GCT-derived cell line (KGN) was transduced with lentiviral vectors expressing small hairpin RNAs targeting GATA4 or transfected with adenovirus expressing either wild-type or dominant negative mutant GATA4. We found that receptors DR4 and DR5 are expressed in a vast majority of GCTs as well as in primary GCT cultures, and that TRAIL induces apoptosis in the primary GCT cultures. Moreover, we showed that overexpressing GATA4 protects GCTs from TRAIL-induced apoptosis in vitro , whereas disrupting GATA4 function induces apoptosis and potentiates the apoptotic effect of TRAIL administration. Our results demonstrate that the TRAIL pathway is functional in GCT cells, and suggest that transcription factor GATA4 may function as a survival factor in this ovarian malignancy.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-01-2012
Abstract: Although loss of epithelial integrity is a hallmark of advanced cancer, it remains poorly understood whether genetic alterations corrupting this integrity causally facilitate tumorigenesis. We show that conditional deletion of tumor suppressor gene Lkb1 (Par-4) in the mammary gland compromises epithelial integrity manifested by mislocalization of cell polarity markers, lateralization of tight junctions, deterioration of desmosomes and basement membrane (BM), and hyperbranching of the mammary ductal tree. We identify the desmosomal BM remodelling serine protease Hepsin as a key factor mediating Lkb1 loss-induced structural alterations in mammary epithelium and BM fragmentation. Although loss of Lkb1 alone does not promote mammary tumorigenesis, combination of Lkb1 deficiency with oncogenic c-Myc leads to dramatic acceleration in tumor formation. The results coupling Lkb1 loss-mediated epithelial integrity defects to mislocalization of serine protease Hepsin and to oncogenic synergy with c-Myc imply that Lkb1 loss facilitates oncogenic proliferation by releasing epithelial cells from structural BM boundaries.
Publisher: Springer Science and Business Media LLC
Date: 28-03-2022
DOI: 10.1038/S41467-022-29183-X
Abstract: Carbohydrates, proteins and lipids are essential nutrients to all animals however, closely related species, populations, and in iduals can display dramatic variation in diet. Here we explore the variation in macronutrient tolerance in Drosophila melanogaster using the Drosophila genetic reference panel, a collection of ~200 strains derived from a single natural population. Our study demonstrates that D. melanogaster , often considered a “dietary generalist”, displays marked genetic variation in survival on different diets, notably on high-sugar diet. Our genetic analysis and functional validation identify several regulators of macronutrient tolerance, including CG10960/GLUT8 , Pkn and Eip75B . We also demonstrate a role for the JNK pathway in sugar tolerance and de novo lipogenesis. Finally, we report a role for tailles s, a conserved orphan nuclear hormone receptor, in regulating sugar metabolism via insulin-like peptide secretion and sugar-responsive CCHamide-2 expression. Our study provides support for the use of nutrigenomics in the development of personalized nutrition.
Publisher: Oxford University Press (OUP)
Date: 27-05-2021
DOI: 10.1093/G3JOURNAL/JKAB171
Abstract: Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an in idual’s genotype. Here, we sought to understand how such gene–diet interactions influenced nutrient storage and utilization, a major determinant of metabolic disease. We subjected 178 inbred strains from the Drosophila genetic reference panel (DGRP) to diets varying in sugar, fat, and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilization that can be robustly measured. Diet influenced the starvation resistance of most strains, but the effect varied markedly between strains such that some displayed better survival on a high carbohydrate diet (HCD) compared to a high-fat diet while others had opposing responses, illustrating a considerable gene × diet interaction. This demonstrates that genetics plays a major role in diet responses. Furthermore, heritability analysis revealed that the greatest genetic variability arose from diets either high in sugar or high in protein. To uncover the genetic variants that contribute to the heterogeneity in starvation resistance, we mapped 566 diet-responsive SNPs in 293 genes, 174 of which have human orthologs. Using whole-body knockdown, we identified two genes that were required for glucose tolerance, storage, and utilization. Strikingly, flies in which the expression of one of these genes, CG4607 a putative homolog of a mammalian glucose transporter, was reduced at the whole-body level, displayed lethality on a HCD. This study provides evidence that there is a strong interplay between diet and genetics in governing survival in response to starvation, a surrogate measure of nutrient storage efficiency and obesity. It is likely that a similar principle applies to higher organisms thus supporting the case for nutrigenomics as an important health strategy.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2019
DOI: 10.1007/S11154-019-09505-Z
Abstract: Indigenous Australians are particularly affected by type 2 diabetes mellitus (T2D) due to both their genetic susceptibility and a range of environmental and lifestyle risk factors. Recent genetic studies link predisposition to some diseases, including T2D, to alleles acquired from archaic hominins, such as Neanderthals and Denisovans, which persist in the genomes of modern humans today. Indo-Pacific human populations, including Indigenous Australians, remain extremely underrepresented in genomic research with a paucity of data examining the impact of Denisovan or Neanderthal lineages on human phenotypes in Oceania. The few genetic studies undertaken emphasize the uniqueness and antiquity of Indigenous Australian genomes, with possibly the largest proportion of Denisovan ancestry of any population in the world. In this review, we focus on the potential contributions of ancient genes athways to modern human phenotypes, while also highlighting the evolutionary roles of genetic adaptation to dietary and environmental changes associated with an adopted Western lifestyle. We discuss the role of genetic and epigenetic factors in the pathogenesis of T2D in understudied Indigenous Australians, including the potential impact of archaic gene lineages on this disease. Finally, we propose that greater understanding of the underlying genetic predisposition may contribute to the clinical efficacy of diabetes management in Indigenous Australians. We suggest that improved identification of T2D risk variants in Oceania is needed. Such studies promise to clarify how genetic and phenotypic differences vary between populations and, crucially, provide novel targets for personalised medical therapies in currently marginalized groups.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-08-2023
Abstract: Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK , misshapen , altered the metabolite profiles and impaired de novo lipogenesis in high sugar–fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.
No related grants have been discovered for Essi Havula.