RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 ,uM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytenic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced[3H]-9cRA from RXR with Ki values of 4 ,uM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways.

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The adult kidney replaces its parenchyma in vivo in steady state and during regeneration by segment-specific clonal cell proliferation.To understand human adult kidney clonal cell growth, we derived tissue from human nephrectomies and performed limiting dilution to establish genuine clonal cultures from one single cell.Clonal efficiency of the human kidney was x%. Remarkably, a single renal cell could give rise to up to 3.3*10(6) cells. Phenotypically, two types of clonal cultures were apparent; a stably proliferating cuboidal epithelial-like appearing (EL) and a rapidly proliferating fibroblast-like appearing (FL). RNA sequencing of all clonal cultures separated FL from EL cultures according to proximal-distal/collecting renal epithelial tubular identity, respectively. Moreover, distinct molecular features in respect to cellcycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers were observed for each clone type. Surprisingly, clonal expansion (>3 months) was sustained in EL clones harboring markers of mature kidney epithelia (high CD24, CDH1, EpCAM, EMA) in contrast to dedifferentiated FL clones (high NCAM1, serpine1), which showed fast lineage amplification and exhausted in a few weeks. Thus, the human adult kidney harbors progenitor cell function in which segment identity and the level of epithelial differentiation dictate clonal characteristics.2 4 . Liu, J., et al., Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation . J Proteome Res, 2019. 18(1): p. 331-340.2 5 . , L., et al., Clear Cell Renal Cell Carcinoma is linked to Epithelial-to-Mesenchymal Transition and to Fibrosis. Physiol Rep, 2017. 5(11.( 2 6 . Sanchez, D.J. and M.C. Simon, Genetic and metabolic hallmarks of clear cell renal cell carcinoma. Biochim Biophys Acta Rev Cancer, 2018. 1870(1): p. 23-31. Landolt2 7 .Buzhor, E., et al., Cell-based therapy approaches: the hope for incurable diseases. Regen Med, 2014. 9(5): p. 649-72. 2 8 . Chuang, C.H., et al., Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 2017. 23(3): p. 291-300.

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