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Constitutive androstane receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid, and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared with males. Early (1 day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2 weeks) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to proinflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle induced carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver nonparenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease. [ABSTRACT FROM AUTHOR]

Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/β; BMAL1 induces REV-ERBα/β, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/β activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/β agonist SR-9009 (100 mg·kg -1 ·day -1 for 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3β signaling). Collectively, these observations highlight a role for REV-ERBα/β as a mediator of a subset of circadian clock-controlled processes in the heart.

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg -1 ·wk -1 ), and the second group was injected with 7.5 mg·kg -1 ·wk -1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD 2 , PGE 2, and 6-keto-PG 2α ) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169 + metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169 + cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.