ABSENCE OF THERMAL TRANSIENT RECEPTOR-POTENTIAL (TRP) CHANNELS CONTRIBUTES TO CIRCADIAN DISRUPTION IN THE LIVER

Physiology 2019 (Aberdeen, UK) (2019) Proc Physiol Soc 43, PC185

Poster Communications: ABSENCE OF THERMAL TRANSIENT RECEPTOR-POTENTIAL (TRP) CHANNELS CONTRIBUTES TO CIRCADIAN DISRUPTION IN THE LIVER

M. N. Moraes1, L. V. de Assis2, A. D. Castrucci2

1. Anhembi Morumbi University, São Paulo, SP, Brazil. 2. Physiology, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil.

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Most, if not all, physiological processes, including metabolic events, are under the control of the circadian system, and thus display an oscillatory profile throughout the day, which is ensured by the presence of the clock molecular machinery. Transient receptor potential (TRP) channels are involved in thermogenesis, and energy balance control. We investigated the role of TRPA1, TRPM8 and TRPV1 channels by assessing clock genes and clock-controlled genes (CCGs) in the liver of wild type (WT) and TrpA1, TrpM8 and TrpV1 KO mice. Two to 4 month old mice were single housed at 22 ± 2oC, under 12:12 LD cycle, euthanized at ZT2 and ZT14 (2 hours after lights on and off, respectively), and the liver was collected for further quantitative PCR. Differences between time points of the same genotype or among genotypes at same time point were determined by Two-Way ANOVA followed by Bonferroni post-test. The biological relevance of TRP channels in human liver were analyzed applying Genes Set Enrichment Analysis (GSEA) in transcriptome from Genotype-Tissue Expression (GTEx). TrpM8 and TrpV1 showed an oscillatory profile in the liver of C57BL/6J WT mice. Removal of TRPM8 or TRPV1 channel did not impair the circadian oscillation of Per1; conversely, Bmal1 expression was markedly and partially reduced in TrpM8 and TrpV1 KO mice, respectively, when compared to WT mice. Surprisingly, B6;129 mice do not express TrpV1 channel in the liver, and the expression of TrpA1 displayed a circadian variation compared to C57BL/6J WT and TrpV1 KO mice. Since the expression of TrpA1 was altered in the absence of TrpV1, we investigated the role of TRPA1 channel in the hepatic circadian physiology. Oscillatory profiles of liver Per1, Bmal1, and Glut2 were modified in the absence of both TrpA1 and TrpV1 when compared to B6;129 WT. Thus, our results reveal a new role for TRPA1/TRPV1 channels in the liver, where they participate in the regulation of clock genes and glucose transporter. Corroborating our in vivo mouse data, human bioinformatics demonstrated that TRPA1 channel plays a novel role in liver physiology. In conclusion, disruption of the clock machinery is closely associated with metabolic disorders, and thus pharmacological intervention in clock genes and/or TRP channels may become a promising alternative therapeutic target to treat metabolic disorders.



Where applicable, experiments conform with Society ethical requirements.

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