American Diabetes Association
Online_Appendix_Jersin_etal.pdf (1.84 MB)

Role of the Neutral Amino Acid Transporter Slc7a10 in Adipocyte Lipid Storage, Obesity and Insulin Resistance

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Version 2 2023-03-15, 15:23
Version 1 2021-01-06, 21:26
posted on 2023-03-15, 15:23 authored by Ada AdminAda Admin, Regine Å. Jersin, Divya Sri Priyanka Tallapragada, André Madsen, Linn Skartveit, Even Fjære, Adrian McCann, Laurence Lawrence-Archer, Aron Willems, Jan-Inge Bjune, Mona S. Bjune, Villy Våge, Hans Jørgen Nielsen, Håvard Luong Thorsen, Bjørn Gunnar Nedrebø, Christian Busch, Vidar M. Steen, Matthias Blüher, Peter Jacobson, Per-Arne Svensson, Johan Fernø, Mikael Rydén, Peter Arner, Ottar Nygård, Melina Claussnitzer, Ståle Ellingsen, Lise Madsen, Jørn V. Sagen, Gunnar Mellgren, Simon N. Dankel
Elucidation of mechanisms that govern lipid storage, oxidative stress and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter 1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA-sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance and type 2 diabetes.


Bergens Forskningsstiftelse Diabetesforbundet KG Jebsen Center for Diabetes Research x Norges Forskningsråd 245979/F50 263124 / F20 Novo Nordisk Fonden Samarbeidsorganet Helse-Vest


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