Biology subjects

Dumais, E.

Publications and source records attributed to Dumais, E..

3 recordsLinked to original sources

bioRxiv2026

Circadian disruption alters hepatic calcium hemostasis, endocannabinoidome and mitochondria through N -docosahexaenoyl ethanolamide-GPR110 signaling

Circadian rhythm disruption is associated with metabolic and inflammatory disorders; however, the mechanisms linking circadian dysfunction to endocannabinoidome (eCBome) signaling and mitochondrial metabolism remain unclear. In our previous in vivo study, constant light exposure altered hepatic eCBome profiles, reduced N-acylethanolamines (NAEs), increased monoacylglycerols (MAGs), and elevated inflammatory cytokines. Here, we investigated the underlying mechanisms using CRISPR/Cas9-generated BMAL1 knockout (KO) HepG2 cells as an in vitro model of circadian alteration. The BMAL1 KO model showed broad lipid remodeling characterized by increased fatty acids, prostaglandins, and MAGs together with reduced NAEs and enhanced lipid accumulation. These changes were accompanied by increased inflammatory signaling and cytokine production. Among the assessed genes, GPR110 was significantly altered in mice exposed to constant light (in vivo study) and BMAL1 KO model and emerged as a potential mediator linking circadian signaling to mitochondrial function. BMAL1 KO cells also exhibited significantly increased calcium (Ca{superscript 2}+) levels in mitochondria and the endoplasmic reticulum (ER), along with attenuation of mitochondrial and glycolytic ATP production. BMAL1KO did not abolish the rhythmicity of NAEs level over 24 hours from medium deprivation and read ministration except for N-docosahexaenoyl-ethanolamide (DHEA). Further, experiments showed that DHEA acts through GPR110 and suppress inflammatory lipid-associated pathways, enhances ATP production, and increases mitochondrial and ER Ca{superscript 2}+ accumulation and inflammatory signaling. Together, these mitochondrial Ca{superscript 2}+ signaling, and inflammation in hepatocytes, highlighting DHEA-GPR110 signaling as a potential regulator of hepatic metabolic homeostasis. HighlightsCircadian disruption increases hepatic monoacylglycerols and decreases N-acylethanolamines. Circadian disruption decreases ATP production and enhances mitochondrial and endoplasmic reticulum Ca{superscript 2}+ levels in hepatocytes DHEA-GPR110 signaling regulates hepatocytes mitochondrial Ca{superscript 2}+ dynamics and ATP production GPR110-mediated Ca{superscript 2}+ signaling significantly alters hepatocytes glycolysis and glycolytic ATP production

Cell Biology↗

bioRxiv2025

Circadian Disruption Elicits Sex-Specific Gut Microbiota, Endocannabinoidome and Lipid Mediator Responses

Circadian disruption is a pervasive environmental stressor that increases susceptibility to metabolic and inflammatory diseases, yet sex-specific adaptive strategies remain poorly understood. Here, we show that constant light (LL) exposure alters gut microbial communities and triggers sex- and tissue-specific host adaptations in the endocannabinoidome and other bioactive lipids. Using 16S rRNA sequencing, short chain fatty acid (SCFA) quantification, LC-MS/MS lipidomics, and cytokine profiling, we identified divergent coping strategies across brain, metabolic and intestinal tissues and reproductive organs. In females, LL induced microbial restructuring, with enrichment of Rikenellaceae, Butyricicoccaceae, and Alistipes, but these changes were uncoupled from short-chain fatty acids (SCFA) output. Also, they engaged N-acylethanolamine (NAE)-driven endocannabinoidome signaling in the brain (AEA, DHEA, OEA, PEA, SEA), accompanied by omega-6 prostaglandin upregulation and increased cytokines (IL-5, IFN-{gamma}, MIP-2). The 2-monoacyl glycerols (2-MAGs) increased selectively in liver and skeletal muscle, reflecting tissue-specific lipid remodeling. In males, microbial shifts were limited (e.g., Ruminococcaceae depletion, Tuzzerella enrichment), yet LL triggered robust metabolic adaptation resulting in elevated SCFA levels (isobutyric, butyric, isovaleric, valeric acids) in faeces and elevation of several DHA-derived bioactive lipids in different intestinal tissues Few alterations in brain bioactive lipids were found, while several 2-MAGs were elevated skeletal muscles and testes. In contrast, several oxylipins were decreased within subcutaneous but not other adipose tissue depots. Together, the data shows that changes in bioactive lipid levels in response to circadian rhythm disruption are organ- and sex-specific as are alterations in microbiota populations, positioning sex as a key determinant of responses to circadian stress.

biochemistry↗

bioRxiv2024

ATP Citrate Lyase Drives Vascular Remodeling Diseases Development Through Metabolic-Epigenetic Reprograming.

Our study explores the previously uncharted role of ATP-citrate lyase (ACLY) in vascular remodeling within the pulmonary and coronary arteries, providing novel insights into the pathogenesis of pulmonary hypertension and coronary artery diseases. ACLY, involved in de novo lipid synthesis and histone acetylation, has emerged as a key regulator in sustaining vascular smooth muscle cell (VSMC) proliferation and survival. Utilizing human coronary and pulmonary artery tissues, our findings reveal an upregulation of ACLY expression during vascular remodeling processes. Inhibition of ACLY, achieved through pharmacological and molecular interventions in humans primary cultured VSMCs, leads to decreased proliferation, migration, and resistance to apoptosis. Mechanistically, these effects are associated with diminished glycolysis, lipid synthesis, GCN5-dependent histone acetylation, and FOXM1 activation. In vivo experiments, combining pharmacological and VSMC-specific ACLY knockout mice, ACLY inhibition demonstrates its efficacy in mitigating coronary artery remodeling and reducing pulmonary hypertension. Notably, initiating ACLY inhibition post-disease onset reverses pathological conditions, positioning ACLY as a promising therapeutic target. Human ex vivo tissue culture further supports our findings, showing reduced vascular remodeling in cultured human coronary artery rings and a reversal of pulmonary artery remodeling in precision-cut lung slices upon ACLY inhibition. This study introduces a groundbreaking concept, linking disparate abnormalities in vascular diseases to a common pathogenetic denominator, ACLY. The identified "multiple hit" therapeutic approach presents potential targets for addressing complex vascular diseases, offering avenues for future clinical interventions. ONE SENTENCE SUMMARYOur study delineates the pivotal role of ATP-citrate lyase in orchestrating vascular remodeling, establishing it as a compelling translational target for therapeutic interventions in pulmonary hypertension and coronary artery disease.

physiology↗