Biology subjects

Plutzky, J.

Publications and source records attributed to Plutzky, J..

3 recordsLinked to original sources

bioRxiv2020

Cold-mediated regulation of systemic retinol transport controls adipose tissue browning

Browning of white fat reduces obesity in many preclinical models. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue (AT), however the physiologic importance of systemic retinoid metabolism for AT browning is unknown. Here we show that cold stimulation in mice and humans increases circulating retinol and its plasma transporter, retinol binding protein (RBP). Cold exposure shifts retinol abundance from liver towards subcutaneous white AT which correlates with enhanced thermogenic gene transcription. Cold-mediated retinoid flux is abrogated in Rbp deficient (Rbp-/-) mice and AT browning is dramatically impaired, which renders Rbp-/- mice cold intolerant. Rbp deficiency attenuates cold-induced lipid clearance due to decreased oxidative capacity. In humans, cold-mediated retinol increase is associated with enhanced lipid utilization. Retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In conclusion, coordinated retinol delivery is essential for cold-induced thermogenic programming of white fat.

physiology↗

bioRxiv2019

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

Traditionally a pharmacologic target for antipsychotic treatment, the sigma-2 receptor (S2R) was recently implicated in cholesterol homeostasis. Here we investigated the transcriptional regulation of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, 4) upon cholesterol perturbation.\n\nCytosolic cholesterol deprivation was induced using an export blocker of lysosomal cholesterol in ARPE19 cells. This condition upregulated mRNA and protein levels of S2R, and of SREBP2 but not SREBP1, transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD4 (though widely deemed as a master regulator) or BRD3 prevented S2R upregulation induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, BRD2 co-immunoprecipitated with the SREBP2 transcription-active N-terminal domain, and chromatin immunoprecipitation-qPCR showed a BRD2 occupancy at the S2R gene promoter.\n\nIn summary, this study reveals a novel BRD2/SREBP2 cooperative regulation of S2R transcription in response to cytosolic cholesterol deprivation, thus shedding new light on epigenetic control of cholesterol biology.

biochemistry↗

bioRxiv2019

The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation

BackgroundVein-graft bypass is commonly performed to overcome atherosclerosis but is limited by high failure rates, principally due to neointimal wall thickening. Recent studies reveal that endothelial-mesenchymal transition (EndoMT) is critical for vein-graft neointima formation. BETs are a family of Bromo/ExtraTerminal domains-containing epigenetic reader proteins (BRD2, BRD3, BRD4). They bind acetylated histones through their unique tandem bromodomains (BD1, BD2), facilitating transcriptional complex formation and cell-state transitions. The role for BETs, including individual BRDs and their unique BDs, is not well understood in EndoMT and neointimal formation.\n\nMethods and ResultsRepression of BRD4 expression abrogated TGF{beta}1-induced EndoMT, with greater effects than BRD2 or BRD3 knockdown. An inhibitor selective for BD2 in all BETs, but not that for BD1, blocked EndoMT. Moreover, expression of a dominant-negative BRD4-specific BD2 fully abolished EndoMT. Concordantly, BRD4 knockdown repressed TGF{beta}1-stimulated increase of ZEB1 protein - a transcription factor integral in EndoMT. In vivo, lentiviral gene transfer of either BRD4 shRNA or dominant negative BRD4-specific BD2 mitigated neointimal development in rat jugular veins grafted to carotid arteries.\n\nConclusionsOur data reveal the BD2 domain of BRD4 as a determinant driving EndoMT in vitro and neointimal formation in vivo. These findings provide new insight into BET biology, while offering prospects of specific BET domain targeting as an approach to limiting neointima and extending vein graft patency.

pathology↗