Biology subjects

Yousefzadeh, M. J.

Publications and source records attributed to Yousefzadeh, M. J..

3 recordsLinked to original sources

bioRxiv2026

Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver

ObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. MethodsMice with or without hepatocyte cyclin D1 (D1fl/fl or D1{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging. HighlightsO_LICyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression. C_LIO_LIAcute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1. C_LIO_LIHepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation. C_LIO_LICyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans. C_LI

physiology↗

bioRxiv2024

Fisetin extends lifespan in a murine model of recessive dystrophic epidermolysis bullosa

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genodermatosis characterized clinically by extensive inflammation, cutaneous destruction, and fibrosis that demonstrates properties similar to rapid skin aging. As tissue ages, it accumulates cellular damage and exhaustion leading to a state of senescence. Cellular senescence is an aging or disease-related phenomenon of stable exit from the cell cycle that leads to an increased inflammatory phenotype. RDEB and other EB subsets of patients need an adjunct to or alternate therapy that addresses the issues of inflammation, pain, and pruritus. Fisetin is a safe, naturally occurring compound proven to be effective at sensitizing senescent cells to cell death and ameliorating senescence-associated inflammation. In this paper, we demonstrate fisetins ability to increase survival and reduce senescent cell burden in a hypomorphic mouse model of RDEB.

molecular biology↗

bioRxiv2024

Clonal dynamics and somatic evolution of haematopoiesis in mouse

Haematopoietic stem cells maintain blood production throughout life. While extensively characterised using the laboratory mouse, little is known about how the population is sustained and evolves with age. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1845 single cell-derived colonies, and used phylogenetic analysis to infer the ontogeny and population dynamics of the stem cell pool. Mouse stem cells and progenitors accrue [~]45 somatic mutations per year, a rate only about 2-fold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns reveal that stem and multipotent progenitor cell pools are both established during embryogenesis, after which they independently self-renew in parallel over life. The stem cell pool grows steadily over the mouse lifespan to approximately 70,000 cells, self-renewing about every six weeks. Aged mice did not display the profound loss of stem cell clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing revealed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations and exhibited a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.

genomics↗