期刊
JOURNAL OF LIPID RESEARCH
卷 61, 期 10, 页码 1328-1340出版社
ELSEVIER
DOI: 10.1194/jlr.RA120000875
关键词
sphingosine-1-phosphate; sphingolipid; high-fat diet; obesity; metabolic disease; adipose; hepatocyte; lipotoxicity; cross-talk
资金
- US Department of Veterans Affairs Merit Award [2I0BX000200]
- National Institutes of Health [1R01HL117233, 1R01HL151243]
- Cell and Molecular Imaging Shared Resource Center, Hollings Cancer Center, Medical University of South Carolina [S10-OD-018113]
- Medical University of South Carolina Proteogenomics Facility
- Medical University of South Carolina Histology and Immunohistochemistry Laboratory
Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depletedSphk1from adipocytes in mice (SK1(fatKO)) and placed them on a HFD. In contrast to our initial hypothesis, SK1(fatKO)mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1(fatKO)mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.
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