Autotaxin (ATX) is a secreted enzyme that generates the bioactive lipid lysophosphatidic acid (LPA). We generated mice with global inducible post-natal inactivation or adipose-specific loss of the Enpp2 gene encoding ATX. The animals are phenotypically unremarkable and exhibit differences in adipocyte size and adipose tissue expression of inflammatory genes after high fat feeding without gross differences in fat distribution or body mass. Surprisingly, both models of Enpp2- deficiency exhibited marked protection from high fat diet-induced hepatic steatosis. This phenotype was not associated with differences in dietary fat absorption but may be accounted for by differences in hepatic expression of genes involved in de novo synthesis of triglycerides. These findings suggest that pharmacological inhibition of ATX might be protective against hepatic steatosis.
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This material is the result of work supported in part with resources and the use of facilities at the Lexington VA Medical Center, supported in part by VA merit Award # BX002769 (SSS) and CX001550 (AJM) from the United States (U.S.) Department of Veterans Affairs. This project was supported by a grant from the Heart Lung and Blood Institute R01HL120507 (SSS) and by an IDeA award from the National Institute of General Medical Sciences P20GM103527 (SSS) of the National Institutes of Health.
All relevant data are within the paper and its Supporting Information files.
S1 Table. TaqMan gene expression (ThermoFisher) assays. https://doi.org/10.1371/journal.pone.0208099.s001 (PPTX)
S1 Fig. Post-natal reductions in ATX expression with MX1-Cre mediated deletion. https://doi.org/10.1371/journal.pone.0208099.s002 (PPTX)
S2 Fig. Effect of global post-natal reductions in ATX on liver gene expression. https://doi.org/10.1371/journal.pone.0208099.s003 (PPTX)
S3 Fig. Adipose-specific reductions in ATX expression. https://doi.org/10.1371/journal.pone.0208099.s004 (PPTX)
S4 Fig. Effect of adipose-specific reductions in ATX on liver gene expression. https://doi.org/10.1371/journal.pone.0208099.s005 (PPTX)
Brandon, J. Anthony; Kraemer, Maria; Vandra, Julia; Halder, Suchismita; Ubele, Margo F.; Morris, Andrew J.; and Smyth, Susan S., "Adipose-Derived Autotaxin Regulates Inflammation and Steatosis Associated with Diet-Induced Obesity" (2019). Gill Heart & Vascular Institute Faculty Publications. 18.
S1 Table. TaqMan gene expression (ThermoFisher) assays.
journal.pone.0208099.s002.pptx (125 kB)
S1 Fig. Post-natal reductions in ATX expression with MX1-Cre mediated deletion.
journal.pone.0208099.s003.pptx (63 kB)
S2 Fig. Effect of global post-natal reductions in ATX on liver gene expression.
journal.pone.0208099.s004.pptx (106 kB)
S3 Fig. Adipose-specific reductions in ATX expression.
journal.pone.0208099.s005.pptx (78 kB)
S4 Fig. Effect of adipose-specific reductions in ATX on liver gene expression.