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The Autonomous Hepatocyte Clock Controls Acetaminophen Bioactivation and Chronotoxicity [Kidney]

ABSTRACT: The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms, possibly through transcriptional regulation of cytochrome p450-oxidoreductase (Por). 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which kidney RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.

ORGANISM(S): Mus musculus

SUBMITTER: Brian Johnson

PROVIDER: E-GEOD-34443 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The Autonomous Hepatocyte Clock Controls Acetaminophen Bioactivation and Chronotoxicity [Liver]

Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms. 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which liver RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.

2013-08-30 | E-GEOD-34442 | biostudies-arrayexpress

The Autonomous Hepatocyte Clock Controls Acetaminophen Bioactivation and Chronotoxicity [Liver]

2013-08-30 | GSE34442 | GEO

The Autonomous Hepatocyte Clock Controls Acetaminophen Bioactivation and Chronotoxicity [Kidney]

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Circadian temporal profiling of MMH-D3 hepatocytes

Project description:The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in MMH-D3 hepatocytes, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that many rhythms can be driven by the cell-autonomous clock and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both co-phasic and anti-phasic organization within a protein-protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase (Odc1) and spermidine synthase (Srm). Metabolic profiling revealed that the enzymatic product of SRM, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis. Samples were collected every 2 hours for a duration of 46 hours from differentiated MMH-D3 hepatocytes synchronized via serum shock. Cells were synchronized by serum shock and incubated for 12 hours, and then samples were collected every 2 hours from 12 hours post-serum shock to 58 hours post-serum shock, for a total of 24 samples.

2011-11-03 | E-GEOD-31049 | biostudies-arrayexpress

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The Hepatocyte Clock and Feeding Interdependently Control Chrono-Homeostasis of Multiple Liver Cell Types (single nuclei RNA-seq)

Project description:Most cells in the body contain a cell autonomous molecular clock, but the requirement of peripheral clocks for circadian rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERBa and b in adult mouse hepatocytes caused the loss of circadian rhythmicity of many liver genes, as expected, but also led to maintained and even gained rhythmicity of other genes without altering feeding behavior. The loss of REV-ERBs from hepatocytes leads to an exaggerated circadian rhythm of de novo lipogenesis and serum triglyceride levels. It is increasingly recognized that liver function is also influenced by non-hepatocytic cells, and remarkably the loss of REV-ERBs in hepatocytes remodeled the circadian transcriptomes of multiple cell types within the liver without altering their core clocks, indicating that hepatocytes communicated time signals to the non-hepatocytic cells. Finally, alteration of food availability, which is the dominant zeitgeber in the liver, demonstrated strong interdependence of the cell-autonomous hepatocyte clock mechanism and non-cell-autonomous environmental change. Together these studies reveal the interdependence of endogenous hepatocyte clocks and feeding entrainment on the regulation of circadian rhythms of multiple cell types in the liver.

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The Hepatocyte Clock and Feeding Interdependently Control Chrono-Homeostasis of Multiple Liver Cell Types (ATAC-seq)

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The Hepatocyte Clock and Feeding Interdependently Control Chrono-Homeostasis of Multiple Liver Cell Types (RNA-seq)

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Circadian Proteomics Landscape of Mouse Livers Organized by Time-restricted Feeding: Proteomics

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2023-08-22 | PXD038276 | Pride

Clock regulation of metabolites reveals coupling between transcription and metabolism

Project description:The circadian clock is intricately connected with metabolism, however the precise details of these connections are incomplete. Here we used high temporal resolution metabolite profiling to determine circadian regulation of mouse liver and cell autonomous metabolism. In mouse liver, we found ~50% of metabolites were circadian, with strong enrichment of the nucleotide, amino acid, and methylation pathways. In U2OS cells, 27% of metabolites were circadian, including amino acids and NAD biosynthesis, also clock controlled in liver. To assess whether cell autonomous metabolite rhythms were clock-dependent, we used RNAi to perturb Bmal1, Cry1, and Cry2. Bmal1 knockdown eliminated most metabolite rhythms, while Cry1 generally shortened and Cry2 lengthened rhythms. Surprisingly, we found Cry1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite and transcriptional rhythms. These results provide the first comprehensive views of circadian liver and cell autonomous metabolism.

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