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Abel J Batty, Jinhui Li, Xiantao Wang, William E Ackerman, Sean G Kirk, William M White, Xianxi Wang, Dimitrios Anastasakis, Lobelia Samavati, Irina Buhimschi, Leif D Nelin, Markus Hafner, Yusen Liu, Dysregulation of Lipid Metabolism during Gram-Negative Sepsis in Mkp-1 Deficient Mice, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 187.2, https://doi.org/10.4049/jimmunol.202.Supp.187.2
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Abstract
Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gramnegative sepsis by deactivating p38 and JNK. We have previously shown that Mkp-1 +/+ mice, but not Mkp-1 −/− mice, exhibit hypertriglyceridemia and hepatic glycogen depletion 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 global gene expression profile by RNA-seq in the livers. 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 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 down-regulation 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 profound change in metabolic gene expression programs and Mkp-1 plays an important role in this process.
