PUBLICATION
Role of the Neutral Amino Acid Transporter Slc7a10 in Adipocyte Lipid Storage, Obesity and Insulin Resistance
- Authors
- Jersin, R.Å., Priyanka Tallapragada, D.S., Madsen, A., Skartveit, L., Fjære, E., McCann, A., Dyer, L., Willems, A., Bjune, J.I., Bjune, M.S., Våge, V., Nielsen, H.J., Thorsen, H.L., Nedrebø, B.G., Busch, C., Steen, V.M., Blüher, M., Jacobson, P., Svensson, P.A., Fernø, J., Rydén, M., Arner, P., Nygård, O., Claussnitzer, M., Ellingsen, S., Madsen, L., Sagen, J.V., Mellgren, G., Dankel, S.N.
- ID
- ZDB-PUB-210109-12
- Date
- 2021
- Source
- Diabetes 70(3): 680-695 (Journal)
- Registered Authors
- Ellingsen, Ståle
- Keywords
- none
- MeSH Terms
-
- 3T3-L1 Cells
- Adipocytes/metabolism*
- Amino Acid Transport System y+/genetics
- Amino Acid Transport System y+/metabolism*
- Animals
- Blotting, Western
- Diabetes Mellitus, Type 2/metabolism
- Genotype
- Glutathione/metabolism
- Humans
- Insulin Resistance/physiology
- Mice
- Obesity/metabolism*
- Obesity/physiopathology*
- Reactive Oxygen Species/metabolism
- Sequence Analysis, RNA
- Zebrafish
- PubMed
- 33408126 Full text @ Diabetes
Citation
Jersin, R.Å., Priyanka Tallapragada, D.S., Madsen, A., Skartveit, L., Fjære, E., McCann, A., Dyer, L., Willems, A., Bjune, J.I., Bjune, M.S., Våge, V., Nielsen, H.J., Thorsen, H.L., Nedrebø, B.G., Busch, C., Steen, V.M., Blüher, M., Jacobson, P., Svensson, P.A., Fernø, J., Rydén, M., Arner, P., Nygård, O., Claussnitzer, M., Ellingsen, S., Madsen, L., Sagen, J.V., Mellgren, G., Dankel, S.N. (2021) Role of the Neutral Amino Acid Transporter Slc7a10 in Adipocyte Lipid Storage, Obesity and Insulin Resistance. Diabetes. 70(3):680-695.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping