| 1. |
- Lindberg, Johan, 1985-
(författare)
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Localic Categories of Models and Categorical Aspects of Intuitionistic Ramified Type Theory
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis contains three papers, all in the general area of categorical logic, together with an introductory part with some minor results and proofs of known results which does not appear to be (easily) available in the literature.In Papers I and II we investigate the formal system Intuitionistic Ramified Type Theory (IRTT), introduced by Erik Palmgren, as an approach to predicative topos theory. In Paper I we construct and study the category of "local sets" in IRTT, including an extension with inductive definitions. We there also give a model of IRTT in univalent type theory using h-sets. In Paper II we adapt triposes and hyperdoctrines to the ramified setting. These give a categorical semantics for certain formal languages ramified in the same way as IRTT.Paper III, which is part of a joint project with Henrik Forssell, concerns logical aspects of the localic groupoid/category representations of Grothendieck toposes that originate from the work of Joyal and Tierney. Working constructively, we give explicit logical descriptions of locales and localic categories used for representing classifying toposes of geometric theories. Aspects of these descriptions are related to work by Coquand, Sambin et al in formal topology, and we show how parts of their work can be captured and extended in our framework.
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| 2. |
- Palmgren, Henrik
(författare)
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Cell Membrane Homeostasis in Mammals - The roles of ADIPOR2 and TLCD1 & 2
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ten nanometers. That is the approximate thickness of the plasma membrane that separates the extracellular space from the entire cellular machinery. An asymmetrical bilayer consisting of predominantly phospholipids in which proteins and carbohydrates are anchored and exert their function. Together, these components determine the viscosity, thickness, fluidity, permeability and packing of the plasma membrane, which is constantly maintained within a near-optimal chemical composition for proper function, a phenomenon also known as membrane homeostasis. Dietary fatty acids become the building block for the major component of the membrane bilayer, namely the phospholipids, and its composition can reflect the composition in the food, giving some validity to the term “you are what you eat”. To mitigate the huge variation in dietary fatty acids ending up in the membrane, it is reasonable to believe that regulatory mechanisms exist that adjust the fatty acid composition when required. Surprisingly, not much is known regarding how such adaptive responses regulate membrane fatty acid composition on a molecular level. Within this thesis, novel insights into such regulatory mechanisms are presented. Founded on genetic modifications using CRISPR/Cas9, lipidomic analyses, and membrane fluidity measurements, we build upon previous work and provide further evidence implicating the mammalian adiponectin receptor 2 (ADIPOR2) as a master regulator of membrane homeostasis. Human cells that lack ADIPOR2 show a dramatic vulnerability to saturated fat (SFA) exposure, leading to a defective translational response, increased ER stress, impaired mitochondrial respiration, and importantly, a massive increase in SFA-containing phospholipids. By exploiting this phenotype, genetic ablation of ADIPOR2 in human and mouse pre-adipocytes led to cells with drastic elevation in SFA-containing phospholipids. These were deployed to study the effect of phospholipid saturation on insulin signaling in vitro and in vivo. Surprisingly, both human and mouse adipocytes showed normal insulin signaling despite excess SFA content in their phospholipids, thus highlighting the robustness of adipocytes in lipid handling. Separately, genetic suppressors of SFA vulnerability in PAQR-2 (homolog to mammalian ADIPOR2) deficient C. elegans worms, revealed a novel protein dubbed FLD-1 that influences the amount of fluidizing, long-chain polyunsaturated fatty acids (PUFAs) in membrane phospholipids. Further studies in transgenic mice, lacking the mammalian homologs TLCD1 and TLCD2, led to elucidating the mechanism of action of these proteins, namely that they regulate the incorporation of monounsaturated fatty acids (MUFAs) at the sn-1 position of phosphatidylethanolamines. In parallel, another genetic suppressor to the SFA vulnerability of PAQR-2 knockouts was discovered, namely ACS-13, that was shown to regulate mitochondrial activation of long-chain PUFAs, a function conserved in the human homolog ACSL1. Taken together, this thesis provides new insight into the mechanisms that regulate the fatty acid composition of cellular membranes and that are crucial for the ability of cells to maintain fluid membranes in the face of fluctuating levels of dietary fatty acids.
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| 3. |
- Palmgren, Henrik, et al.
(författare)
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Elevated Adipocyte Membrane Phospholipid Saturation Does Not Compromise Insulin Signaling
- 2023
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Ingår i: DIABETES. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:10, s. 1350-1363
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Tidskriftsartikel (refereegranskat)abstract
- Increased saturated fatty acid (SFA) levels in membrane phospholipids have been implicated in the development of metabolic disease. Here, we tested the hypothesis that increased SFA content in cell membranes negatively impacts adipocyte insulin signaling. Preadipocyte cell models with elevated SFA levels in phospholipids were generated by disrupting the ADIPOR2 locus, which resulted in a striking twofold increase in SFA-containing phosphatidylcholines and phosphatidylethanolamines, which persisted in differentiated adipocytes. Similar changes in phospholipid composition were observed in white adipose tissues isolated from the ADIPOR2-knockout mice. The SFA levels in phospholipids could be further increased by treating ADIPOR2-deficient cells with palmitic acid and resulted in reduced membrane fluidity and endoplasmic reticulum stress in mouse and human preadipocytes. Strikingly, increased SFA levels in differentiated adipocyte phospholipids had no effect on adipocyte gene expression or insulin signaling in vitro. Similarly, increased adipocyte phospholipid saturation did not impair white adipose tissue function in vivo, even in mice fed a high-saturated fat diet at thermoneutrality. We conclude that increasing SFA levels in adipocyte phospholipids is well tolerated and does not affect adipocyte insulin signaling in vitro and in vivo.
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| 4. |
- Petkevicius, K., et al.
(författare)
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TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis. The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.
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