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      Atrial natriuretic peptide signaling co-regulates lipid metabolism and ventricular conduction system gene expression in the embryonic heart

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          Summary

          It has been shown that atrial natriuretic peptide (ANP) and its high affinity receptor (NPRA) are involved in the formation of ventricular conduction system (VCS). Inherited genetic variants in fatty acid oxidation (FAO) genes are known to cause conduction abnormalities in newborn children. Although the effect of ANP on energy metabolism in noncardiac cell types is well documented, the role of lipid metabolism in VCS cell differentiation via ANP/NPRA signaling is not known. In this study, histological sections and primary cultures obtained from E11.5 mouse ventricles were analyzed to determine the role of metabolic adaptations in VCS cell fate determination and maturation. Exogenous treatment of E11.5 ventricular cells with ANP revealed a significant increase in lipid droplet accumulation, FAO and higher expression of VCS marker Cx40. Using specific inhibitors, we further identified PPARγ and FAO as critical downstream regulators of ANP-mediated regulation of metabolism and VCS formation.

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          Highlights

          • ANP/NPRA and markers of VCS and FAO are enriched in E11.5 trabecular myocardium

          • ANP stimulates VCS cell proliferation and marker expression in primary cell cultures

          • ANP regulates lipid storage, FAO and oxidative metabolism in E11.5 ventricular cells

          • Inhibition of PPARγ or FAO blocks stimulatory effects of ANP on VCS marker expression

          Abstract

          Cell biology; Developmental biology; Systems biology

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          Most cited references79

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          PPAR gamma is required for placental, cardiac, and adipose tissue development.

          The nuclear hormone receptor PPAR gamma promotes adipogenesis and macrophage differentiation and is a primary pharmacological target in the treatment of type II diabetes. Here, we show that PPAR gamma gene knockout results in two independent lethal phases. Initially, PPAR gamma deficiency interferes with terminal differentiation of the trophoblast and placental vascularization, leading to severe myocardial thinning and death by E10.0. Supplementing PPAR gamma null embryos with wild-type placentas via aggregation with tetraploid embryos corrects the cardiac defect, implicating a previously unrecognized dependence of the developing heart on a functional placenta. A tetraploid-rescued mutant surviving to term exhibited another lethal combination of pathologies, including lipodystrophy and multiple hemorrhages. These findings both confirm and expand the current known spectrum of physiological functions regulated by PPAR gamma.
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            Regulation of the pentose phosphate pathway in cancer

            Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
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              Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer.

              Targeting of the nuclear prostaglandin receptor peroxisome proliferator-activated receptor delta (PPARdelta) by homologous recombination results in placental defects and frequent (>90%) midgestation lethality. Surviving PPARdelta(-/-) mice exhibit a striking reduction in adiposity relative to wild-type levels. This effect is not reproduced in mice harboring an adipose tissue-specific deletion of PPARdelta, and thus likely reflects peripheral PPARdelta functions in systemic lipid metabolism. Finally, we observe that PPARdelta is dispensable for polyp formation in the intestine and colon of APC(min) mice, inconsistent with its recently proposed role in the establishment of colorectal tumors. Together, these observations reveal specific roles for PPARdelta in embryo development and adipocyte physiology, but not cancer.
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                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                14 December 2023
                19 January 2024
                14 December 2023
                : 27
                : 1
                : 108748
                Affiliations
                [1 ]Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
                [2 ]Department of Process Engineering and Applied Science, Dalhousie University, Halifax, NS, Canada
                Author notes
                []Corresponding author Kishore.pasumarthi@ 123456dal.ca
                [3]

                Lead contact

                Article
                S2589-0042(23)02825-0 108748
                10.1016/j.isci.2023.108748
                10792247
                38235330
                8c021447-0e5a-4b19-a3db-464167917a26
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 15 May 2023
                : 15 September 2023
                : 12 December 2023
                Categories
                Article

                cell biology,developmental biology,systems biology
                cell biology, developmental biology, systems biology

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