Ablation of Promyelocytic Leukemia Protein (PML) Re-patterns Energy Balance and Protects Mice from Obesity Induced by a Western Diet

Cheng, Xiangguo; Guo, Shuang; Liu, Yu; Chu, Hao; Hakimi, Parvin; Berger, Nathan A.; Hanson, Richard W.; Kao, Hung Ying

doi:10.1074/jbc.m113.487595

Cited by 26 publications

(37 citation statements)

References 49 publications

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“…PML NBdependent activation of peroxisome proliferator-activated receptor (PPAR) g co-activator-1a (PGC-1a), PPAR signaling and fatty acid β-oxidation provided a growth advantage to breast cancer cells (Carracedo et al, 2012) and controlled asymmetric division and maintenance of hematopoietic stem cells . In contrast, PML KO mice had tissue-specific enhancement of both fatty acid b-oxidation and synthesis, increased metabolic rate and resistance to diet-induced obesity (Cheng et al, 2013). Together with these findings, our results suggest that LAP domains associated with nLDs could have a multi-facetted role in lipid homeostasis involving the recruitment of CCTa and Lipin1 to promote PC and TAG synthesis and storage as well as…”

Section: Discussionsupporting

confidence: 67%

Lipid-associated PML domains regulate CCTα, Lipin1 and lipid homeostasis

Lee

Salsman

Foster³

et al. 2020

Preprint

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Nuclear LDs (nLDs) originate at the inner nuclear membrane by a mechanism that involves the promyelocytic leukemia (PML) protein. Here we demonstrate that nLDs in oleate-treated U2OS cells are associated with Lipid-Associated PML (LAP) domains that differ from canonical PML nuclear bodies by the relative absence of SUMO1, SP100 and DAXX. nLDs were also enriched in CTP:phosphocholine cytidylyltransferase a (CCTa), the phosphatidic acid phosphatase Lipin1 and diacylglycerol (DAG). High resolution imaging revealed that LAP domains and CCTa occupy distinct polarized regions on nLDs, and that loss of LAP domains in PML knockout U2OS cells reduced the recruitment of CCTa onto nLDs by its amphipathic a-helical M-domain. The association of Lipin1 and DAG with nLDs was also LAP domain-dependent. The disruption of CCTa and Lipin1 localization on nLDs in PML knockout cells resulted in the inhibition of phosphatidylcholine and triacylglycerol synthesis indicating that LAP domains are a unique PML subdomain involved in nLD assembly and regulation of lipid metabolism.

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Section: Discussionsupporting

confidence: 67%

Lipid-associated PML domains regulate CCTα, Lipin1 and lipid homeostasis

Lee

Salsman

Foster³

et al. 2020

Preprint

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“…Using human biopsy materials and an obese mouse model, Carracedo and Pandolfi et al found that hepatic PML protein levels are increased in obese subjects which strongly correlated with liver steatosis, suggesting a role for PML in hepatic function in response to obese conditions [ 117 ]. Indeed, an earlier study by Cheng and Kao demonstrated that the depletion of Pml in mice decreases liver fatty acid accumulation after long-term Western diet feeding and in turn protects mouse liver from dysplastic nodules [ 118 ]. Dysplastic nodules are histologically visible benign lesions which follow liver steatosis and are viewed as an early stage of cirrhosis and hepatocellular carcinoma (HCC).…”

Section: Physiological and Pathological Role Of Pmlmentioning

confidence: 99%

“…Analyses of the microarray data in PML -depleted HUVECs suggest that PML is involved in the regulation of a large cohort of metabolic gene expression [ 115 , 120 ]. Along the same line, loss of Pml in mice re-patterns glucose and fatty acid metabolism gene expression in metabolically active tissues, such as muscle and liver, increases metabolic rate and resists obese symptoms induced by a Western diet [ 118 ]. It is worthy to note that different results in PML metabolic function and obese predisposition have also been reported [ 115 , 121 ].…”

Section: Physiological and Pathological Role Of Pmlmentioning

confidence: 99%

PML: Regulation and multifaceted function beyond tumor suppression

Hsu

Kao

2018

Cell Biosci

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Promyelocytic leukemia protein (PML) was originally identified as a fusion partner of retinoic acid receptor alpha in acute promyelocytic leukemia patients with the (15;17) chromosomal translocation, giving rise to PML–RARα and RARα–PML fusion proteins. A body of evidence indicated that PML possesses tumor suppressing activity by regulating apoptosis, cell cycle, senescence and DNA damage responses. PML is enriched in discrete nuclear substructures in mammalian cells with 0.2–1 μm diameter in size, referred to as alternately Kremer bodies, nuclear domain 10, PML oncogenic domains or PML nuclear bodies (NBs). Dysregulation of PML NB formation results in altered transcriptional regulation, protein modification, apoptosis and cellular senescence. In addition to PML NBs, PML is also present in nucleoplasm and cytoplasmic compartments, including the endoplasmic reticulum and mitochondria-associated membranes. The role of PML in tumor suppression has been extensively studied but increasing evidence indicates that PML also plays versatile roles in stem cell renewal, metabolism, inflammatory responses, neural function, mammary development and angiogenesis. In this review, we will briefly describe the known PML regulation and function and include new findings.

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“…The PML protein and PML bodies have been shown to function in a number of processes relevant to myogenesis. For example, though skeletal muscle development is not markedly affected in Pml−/− mice, expression of muscle metabolic genes is altered, as is the regulation of cell growth and the retinoic acid pathway [34, 35]. It may be of particular relevance that PML is a regulator of p53-mediated cell death [36].…”

Section: Discussionmentioning

confidence: 99%

Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4

Homma

Beermann

et al. 2016

Skeletal Muscle

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BackgroundNuclear bodies, such as nucleoli, PML bodies, and SC35 speckles, are dynamic sub-nuclear structures that regulate multiple genetic and epigenetic processes. Additional regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, which have been linked to ALS pathology. Previous work showed that mouse cell line myotubes have fewer but larger nucleoli than myoblasts, and we had found that nuclear aggregation of TDP-43 in human myotubes was induced by expression of DUX4-FL, a transcription factor that is aberrantly expressed and causes pathology in facioscapulohumeral dystrophy (FSHD). However, questions remained about nuclear bodies in human myogenesis and in muscle disease.MethodsWe examined nucleoli, PML bodies, SC35 speckles, TDP-43, and FUS in myoblasts and myotubes derived from healthy donors and from patients with FSHD, laminin-alpha-2-deficiency (MDC1A), and alpha-sarcoglycan-deficiency (LGMD2D). We further examined how these nuclear bodies and proteins were affected by DUX4-FL expression.ResultsWe found that nucleoli, PML bodies, and SC35 speckles reorganized during differentiation in vitro, with all three becoming less abundant in myotube vs. myoblast nuclei. In addition, though PML bodies did not change in size, both nucleoli and SC35 speckles were larger in myotube than myoblast nuclei. Similar patterns of nuclear body reorganization occurred in healthy control, MDC1A, and LGMD2D cultures, as well as in the large fraction of nuclei that did not show DUX4-FL expression in FSHD cultures. In contrast, nuclei that expressed endogenous or exogenous DUX4-FL, though retaining normal nucleoli, showed disrupted morphology of some PML bodies and most SC35 speckles and also co-aggregation of FUS with TDP-43.ConclusionsNucleoli, PML bodies, and SC35 speckles reorganize during human myotube formation in vitro. These nuclear body reorganizations are likely needed to carry out the distinct gene transcription and splicing patterns that are induced upon myotube formation. DUX4-FL-induced disruption of some PML bodies and most SC35 speckles, along with co-aggregation of TDP-43 and FUS, could contribute to pathogenesis in FSHD, perhaps by locally interfering with genetic and epigenetic regulation of gene expression in the small subset of nuclei that express high levels of DUX4-FL at any one time.

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Ablation of Promyelocytic Leukemia Protein (PML) Re-patterns Energy Balance and Protects Mice from Obesity Induced by a Western Diet

Cited by 26 publications

References 49 publications

Lipid-associated PML domains regulate CCTα, Lipin1 and lipid homeostasis

Lipid-associated PML domains regulate CCTα, Lipin1 and lipid homeostasis

PML: Regulation and multifaceted function beyond tumor suppression

Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4

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