Upstream Stimulatory Factor Represses the Induction of Carnitine Palmitoyltransferase-Iऔ Expression by PGC-1

Moore, Meredith; Park, Edwards A.; McMillin, Jeanie B.

doi:10.1074/jbc.m210486200

Cited by 39 publications

(28 citation statements)

References 47 publications

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“…Additionally, it has been suggested that USF may play a role in maintaining the chromatin structure environment at promoter sites and, similarly to the PPARs, may switch from activator to repressor depending on which signal transduction pathways are operating (14). In support of our model that USF functions as a repressor of CPT1B in skeletal muscle, others have reported that USF-2 can repress CPT1B expression in rat cardiac muscle in a manner that suggested that USF is part of a molecular switch that fine-tunes CPT1B levels in response to certain stimuli (31,38). In light of these observations, the significant decrease in methylation at the USF binding sites at Ϫ539 and Ϫ174 in HSkMC from obese women in response to lipid treatment, and the contrasting increase in methylation at these sites in muscle cells derived from lean women (Fig.…”

Section: Discussionsupporting

confidence: 66%

Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity

Maples

Brault

Witczak

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-␦ and hepatocyte nuclear factor 4␣ transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity. obesity; DNA methylation; skeletal muscle; lipid metabolism; gene regulation MOUNTING EVIDENCE INDICATES that metabolic diseases such as obesity, type 2 diabetes, and insulin resistance are associated with an inability to oxidize lipids (12) and adjust substrate oxidation according to nutrient availability, termed "metabolic flexibility" (24). These impairments are particularly evident in the severely obese (Class III; BMI Ͼ40 kg/m 2 ), where there is an impaired ability to oxidize lipid (fatty acid oxidation, FAO) in skeletal muscle and an inability to increase skeletal muscle FAO in response to a high-fat diet (3, 25). These decrements likely contribute to ectopic lipid accumulation, which in turn is associated with insulin resistance, weight gain (13), and weight regain after weight loss (46).The molecular mechanisms contributing to this inability to oxidize lipid with severe obesity are, however, not evident. A possible candidate is the expression level of carnitine palmitoyltransferase (CPT1), which mediates the transfer of longchain fatty acids across the outer mitochondrial membrane and is a rate-limiting step in FAO (28). The activity of musclespecific CPT1 (encoded by the CPT1B gene) is reduced in skeletal muscle with obesity, contributing to a decrease in FAO (25). Conversely, overexpression of CPT1 in skeletal muscle...

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Section: Discussionsupporting

confidence: 66%

Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity

Maples

Brault

Witczak

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Therefore, we have shown that rosiglitazone precludes insulin-induced USF protein binding to specific sequences in the FAS promoter, and that this correlates with the inhibition observed in FAS mRNA and protein accumulation. USFs have been reported to interact with PGC-1 [40,41] and with CBP/p300 [42,43], co-activators for many nuclear receptors including PPARγ [44,45]. Competition between USFs and PPARγ for the same co-activator, for which PPARγ bound to rosiglitazone would have a higher affinity, is a possibility to explore in the future.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats

et al. 2005

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Aims/hypothesis: Although thiazolidinediones are now widely used to treat type 2 diabetes, their mechanism of action remains largely unknown. They are agonists for the transcription factor PPARγ, and in addition to their insulin-sensitising effects, they can promote adipogenesis and control gene expression in adipose tissues. We have explored the effect of rosiglitazone on insulin-mediated induction of pivotal genes involved in lipid metabolism and thermogenesis in brown fat. The genes studied were: (1) lipoprotein lipase (lpl), which is involved in lipid uptake; (2) hormone-sensitive lipase (hsl), which mobilises fatty acids from stored triglycerides; (3) fatty acid synthase (fas), which regulates de novo lipogenesis; and (4) the uncoupling proteins (ucp) 1 and 3, which control thermogenesis. Methods: We used fetal rat primary brown adipocytes cultured with insulin, rosiglitazone or both combined. Then, we studied gene expression by northern and western blotting, as well as 'run-on' and gel-shift assays to identify binding of potential transcription factors to the fas promoter. Results: Exposure to rosiglitazone for 24 h induced ucp-1, lpl and hsl gene expression and when rosiglitazone was combined with insulin a synergistic effect on lpl and ucp-3 mRNA expression was produced. These effects were consistent with increased LPL and HSL activities as well as respiration rates, mainly in response to exogenous palmitate. In contrast, treatment with rosiglitazone did not alter FAS mRNA basal levels but prevented the induction elicited by insulin in a time-and dose-dependent manner. Correspondingly diminished FAS protein levels and activity, as well as cellular lipid content, were observed, indicating an antilipogenic action of rosiglitazone in brown adipocytes. Furthermore, rosiglitazone impaired insulin increase in the FAS transcription rate by antagonising insulin-induced binding of upstream stimulatory factors to the E-box consensus sequence in the FAS promoter and insulin-induced binding of activating protein-1. Conclusions/interpretation: Rosiglitazone prevents insulin-induced up-regulation of the main lipogenic enzyme but increases the expression of those enzymes involved in lipid uptake and mobilisation, favouring fatty acid utilisation through uncoupled respiration.

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“…In addition to the roles of MEF2 factors in myogenesis and morphogenesis in the developing heart, MEF2 factors have been implicated in hypertrophic growth of the adult heart in response to stress signaling (Zhang et al, 2002), and in the control of genes involved in cardiac energy metabolism (Czubryt et al, 2003;Moore et al, 2003). Bop expression is maintained in the adult heart, although its functions at that stage remain unknown.…”

Section: Potential Roles Of Mef2 and Bop In The Adult Heartmentioning

confidence: 99%

BOP, a regulator of right ventricular heart development, is a direct transcriptional target of MEF2C in the developing heart

et al. 2005

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The vertebrate heart is assembled during embryogenesis in a modular manner from different populations of precursor cells. The right ventricular chamber and outflow tract are derived primarily from a population of progenitors known as the anterior heart field. These regions of the heart are severely hypoplastic in mutant mice lacking the myocyte enhancer factor 2C (MEF2C) and BOP transcription factors, suggesting that these cardiogenic regulatory factors may act in a common pathway for development of the anterior heart field and its derivatives. We show that Bop expression in the developing heart depends on the direct binding of MEF2C to a MEF2-response element in the Bop promoter that is necessary and sufficient to recapitulate endogenous Bop expression in the anterior heart field and its cardiac derivatives during mouse development. The Boppromoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF2. These findings identify Bopas an essential downstream effector gene of MEF2C in the developing heart, and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives.

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Upstream Stimulatory Factor Represses the Induction of Carnitine Palmitoyltransferase-Iऔ Expression by PGC-1

Cited by 39 publications

References 47 publications

Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity

Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity

Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats

BOP, a regulator of right ventricular heart development, is a direct transcriptional target of MEF2C in the developing heart

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