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Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis

1
Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43215, USA
2
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892, USA
3
Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA
4
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
5
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3904; https://doi.org/10.3390/ijms19123904
Received: 9 November 2018 / Revised: 27 November 2018 / Accepted: 30 November 2018 / Published: 6 December 2018
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Abstract

Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gram-negative sepsis by deactivating p38 and c-Jun N-terminal kinase (JNK). We have previously shown that Mkp-1+/+ mice, but not Mkp-1−/− mice, exhibit hypertriglyceridemia during severe sepsis. However, the regulation of hepatic lipid stores and the underlying mechanism of lipid dysregulation during sepsis remains an enigma. To understand the molecular mechanism underlying the sepsis-associated metabolic changes and the role of Mkp-1 in the process, we infected Mkp-1+/+ and Mkp-1−/− mice with Escherichia coli i.v., and assessed the effects of Mkp-1 deficiency on tissue lipid contents. We also examined the global gene expression profile in the livers via RNA-seq. We found that in the absence of E. coli infection, Mkp-1 deficiency decreased liver triglyceride levels. Upon E. coli infection, Mkp-1+/+ mice, but not Mkp-1−/− mice, developed hepatocyte ballooning and increased lipid deposition in the livers. E. coli infection caused profound changes in the gene expression profile of a large number of proteins that regulate lipid metabolism in wildtype mice, while these changes were substantially disrupted in Mkp-1−/− mice. Interestingly, in Mkp-1+/+ mice E. coli infection resulted in downregulation of genes that facilitate fatty acid synthesis but upregulation of Cd36 and Dgat2, whose protein products mediate fatty acid uptake and triglyceride synthesis, respectively. Taken together, our studies indicate that sepsis leads to a substantial change in triglyceride metabolic gene expression programs and Mkp-1 plays an important role in this process. View Full-Text
Keywords: E. coli infection; sepsis; liver steatosis; hypertriglyceridemia; Mkp-1 E. coli infection; sepsis; liver steatosis; hypertriglyceridemia; Mkp-1
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Li, J.; Wang, X.; Ackerman, W.E., IV; Batty, A.J.; Kirk, S.G.; White, W.M.; Wang, X.; Anastasakis, D.; Samavati, L.; Buhimschi, I.; Nelin, L.D.; Hafner, M.; Liu, Y. Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis. Int. J. Mol. Sci. 2018, 19, 3904.

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