Downregulation Of Metabolic Genes Research Articles

Transcriptomic analysis of AHR wildtype and Knock-out rat livers supports TCDD's role in AHR/ARNT-mediated circadian disruption and hepatotoxicity

Single, high doses of TCDD in rats are known to cause wasting, a progressive loss of 30 to 50% body weight and death within several weeks. To identify pathway perturbations at or near doses causing wasting, we examined differentially gene expression (DGE) and pathway enrichment in centrilobular (CL) and periportal (PP) regions of female rat livers following 6 dose levels of TCDD – 0, 3, 22, 100, 300, and 1000 ng/kg/day, 5 days/week for 4 weeks. At the higher doses, rats lost weight, had increased liver/body weight ratios and nearly complete cessation of liver cell proliferation, signs consistent with wasting. DGE curves were left shifted for the CL versus the PP regions. Canonical Phase I and Phase II genes were maximally increased at lower doses and remained elevated at all doses. At lower doses, ≤ 22 ng/kg/day in the CL and ≤ 100 ng/kg/day, upregulated genes showed transcription factor (TF) enrichment for AHR and ARNT. At the mid- and high-dose doses, there was a large number of downregulated genes and pathway enrichment for DEGs which showed downregulation of many cellular metabolism processes including those for steroids, fatty acid metabolism, pyruvate metabolism and citric acid cycle. There was significant TF enrichment of the hi-dose downregulated genes for RXR, ESR1, LXR, PPARalpha. At the highest dose, there was also pathway enrichment with upregulated genes for extracellular matrix organization, collagen formation, hemostasis and innate immune system. TCDD demonstrates most of its effects through binding the aryl hydrocarbon receptor (AHR) while the downregulation of metabolism genes at higher TCDD doses is known to be independent of AHR binding to DREs. Based on our results with DEG, we provide a hypothesis for wasting in which high doses of TCDD shift circadian processes away from the resting state, leading to greatly reduced synthesis of steroids and complex lipids needed for cell growth, and producing gene expression signals consistent with an epithelial-to-mesenchymal transition in hepatocytes.

Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.

Abstract 2324: A novel oncogene mediated metabolic gene signature predicts breast cancer outcome

Abstract Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in the US, with triple negative breast cancer (TNBC) as the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed nearly all epithelial cancers including triple negative breast cancer. In this study, we demonstrate that loss of Trop2 derives downregulation of metabolic genes. Trop2 oncogene-driven metabolic gene signature is highly elevated in breast cancer patients and predicts poor outcome. Methods: Trop2 expression levels in two independent patient cohorts were analyzed with immunohistochemistry. Trop2 was knockdown in TNBC cell line HCC1806 with shRNA and knock-out in HCC1806 with CRISPR Cas9 system. Trop2 downregulation or gene deletion effect was tested in vitro with colony formation and 3D Matrigel invasion assays. The effect of Trop2 downregulation in tumorigenesis was evaluated in vivo by subcutaneous implantation of control and Trop2 knockdown xenografts. Proteomic changes were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Trop2 led to downregulation of TALDO1 associated metabolic cluster genes which expression levels were further investigated in four independent breast cancer cohort. Finally, the correlation of Trop2 oncogene-driven metabolic gene signature with breast cancer outcome was analyzed in 13 independent breast cancer patient datasets. Results: We demonstrate Trop2 is overexpressed in TNBC, and downregulation of Trop2 disrupts TNBC cell and tumor growth. Through whole proteomic profiling, we discovered a novel metabolic cluster that was downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-driven metabolic gene signature is significantly upregulated in TNBC patients across multiple clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stage of the disease. Conclusion: Our study identifies a new five gene metabolic oncogene-driven signature as a prognostic predictor of breast cancer. Citation Format: Merve Aslan, En-Chi Hsu, Fernando J. Garcia Marques, Abel Bermudez, Michelle Shen, Meghan A. Rice, Shiqin Liu, Robert West, Sharon J. Pitteri, Balázs Győrffy, Tanya Stoyanova. A novel oncogene mediated metabolic gene signature predicts breast cancer outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2324.

The epigenetic regulator G9a attenuates stress-induced resistance and metabolic transcriptional programs across different stressors and species

BackgroundResistance and tolerance are two coexisting defense strategies for fighting infections. Resistance is mediated by signaling pathways that induce transcriptional activation of resistance factors that directly eliminate the pathogen. Tolerance refers to adaptations that limit the health impact of a given pathogen burden, without targeting the infectious agent. The key players governing immune tolerance are largely unknown. In Drosophila, the histone H3 lysine 9 (H3K9) methyltransferase G9a was shown to mediate tolerance to virus infection and oxidative stress (OS), suggesting that abiotic stresses like OS may also evoke tolerance mechanisms. In response to both virus and OS, stress resistance genes were overinduced in Drosophila G9a mutants, suggesting an intact but overactive stress response. We recently demonstrated that G9a promotes tolerance to OS by maintaining metabolic homeostasis and safeguarding energy availability, but it remained unclear if this mechanism also applies to viral infection, or is conserved in other species and stress responses. To address these questions, we analyzed publicly available datasets from Drosophila, mouse, and human in which global gene expression levels were measured in G9a-depleted conditions and controls at different time points upon stress exposure.ResultsIn all investigated datasets, G9a attenuates the transcriptional stress responses that confer resistance against the encountered stressor. Comparative analysis of conserved G9a-dependent stress response genes suggests that G9a is an intimate part of the design principles of stress resistance, buffering the induction of promiscuous stress signaling pathways and stress-specific resistance factors. Importantly, we find stress-dependent downregulation of metabolic genes to also be dependent on G9a across all of the tested datasets.ConclusionsThese results suggest that G9a sets the balance between activation of resistance genes and maintaining metabolic homeostasis, thereby ensuring optimal organismal performance during exposure to diverse types of stress across different species. We therefore propose G9a as a potentially conserved master regulator underlying the widely important, yet poorly understood, concept of stress tolerance.

Abstract 13921: Targeting Receptor-Interacting Protein 140 to Modulate Energy Metabolism in the Failing Heart

The nuclear receptors, peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and their co-regulator PPARγ coactivator-1α (PGC-1α), control postnatal cardiac mitochondrial biogenesis and energy metabolism. During the development of heart failure (HF), the activity of PGC-1/PPAR/ERR is reduced resulting in diminished capacity for fatty acid oxidation (FAO) and ATP production potentially contributing to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PGC-1/PPAR/ERR in skeletal muscle and adipose tissue. We hypothesized that RIP140 represses cardiac energy metabolism in the normal and failing heart. Accordingly, we targeted Nrip1 (encoding RIP140) using a muscle creatinine kinase (MCK)-driven Cre recombinase to generate striated muscle-specific RIP140 knockout (msRIP140 KO) mice. msRIP140 KO mice appeared normal at baseline with no difference in survival or cardiac systolic function compared to littermate controls. RNA-sequence analysis demonstrated that the expression of genes involved in a wide array of mitochondrial energy metabolic pathways including FAO, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and branched-chain amino acid (BCAA) degradation pathways were upregulated in msRIP140 KO ventricles, and in msRIP140 KO skeletal muscle. msRIP140 KO mice exhibited significantly less cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload. Next, cardiac-specific (cs) RIP140 KO mice were generated and subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), an established HF model. csRIP140 KO mice exhibited less cardiac remodeling and systolic dysfunction compared to littermate controls, along with less downregulation of metabolic genes and induction of cardiac stress ( Nppa and Nppb ) and fibrosis response markers ( Tgfb2 and Col3a1 ). We conclude that RIP140 serves as a global co-repressor of cardiac energy metabolic genes in the adult heart and that modulation of RIP140 activity could prove to be a novel therapeutic approach for HF.

Thioredoxin-1 maintains mitochondrial function via mechanistic target of rapamycin signalling in the heart.

Thioredoxin 1 (Trx1) is an evolutionarily conserved oxidoreductase that cleaves disulphide bonds in oxidized substrate proteins such as mechanistic target of rapamycin (mTOR) and maintains nuclear-encoded mitochondrial gene expression. The cardioprotective effect of Trx1 has been demonstrated via cardiac-specific overexpression of Trx1 and dominant negative Trx1. However, the pathophysiological role of endogenous Trx1 has not been defined with a loss-of-function model. To address this, we have generated cardiac-specific Trx1 knockout (Trx1cKO) mice. Trx1cKO mice were viable but died with a median survival age of 25.5 days. They developed heart failure, evidenced by contractile dysfunction, hypertrophy, and increased fibrosis and apoptotic cell death. Multiple markers consistently indicated increased oxidative stress and RNA-sequencing revealed downregulation of genes involved in energy production in Trx1cKO mice. Mitochondrial morphological abnormality was evident in these mice. Although heterozygous Trx1cKO mice did not show any significant baseline phenotype, pressure-overload-induced cardiac dysfunction, and downregulation of metabolic genes were exacerbated in these mice. mTOR was more oxidized and phosphorylation of mTOR substrates such as S6K and 4EBP1 was impaired in Trx1cKO mice. In cultured cardiomyocytes, Trx1 knockdown inhibited mitochondrial respiration and metabolic gene promoter activity, suggesting that Trx1 maintains mitochondrial function in a cell autonomous manner. Importantly, mTOR-C1483F, an oxidation-resistant mutation, prevented Trx1 knockdown-induced mTOR oxidation and inhibition and attenuated suppression of metabolic gene promoter activity. Endogenous Trx1 is essential for maintaining cardiac function and metabolism, partly through mTOR regulation via Cys1483.

The transcriptomic and proteomic responses of Daphnia pulex to changes in temperature and food supply comprise environment-specific and clone-specific elements

BackgroundRegulatory adjustments to acute and chronic temperature changes are highly important for aquatic ectotherms because temperature affects their metabolic rate as well as the already low oxygen concentration in water, which can upset their energy balance. This also applies to severe changes in food supply. Thus, we studied on a molecular level (transcriptomics and/or proteomics) the immediate responses to heat stress and starvation and the acclimation to different temperatures in two clonal isolates of the model microcrustacean Daphnia pulex from more or less stressful environments, which showed a higher (clone M) or lower (clone G) tolerance to heat and starvation.ResultsThe transcriptomic responses of clone G to acute heat stress (from 20 °C to 30 °C) and temperature acclimation (10 °C, 20 °C, and 24 °C) and the proteomic responses of both clones to acute heat, starvation, and heat-and-starvation stress comprised environment-specific and clone-specific elements. Acute stress (in particular heat stress) led to an early upregulation of stress genes and proteins (e.g., molecular chaperones) and a downregulation of metabolic genes and proteins (e.g., hydrolases). The transcriptomic responses to temperature acclimation differed clearly. They also varied depending on the temperature level. Acclimation to higher temperatures comprised an upregulation of metabolic genes and, in case of 24 °C acclimation, a downregulation of genes for translational processes and collagens. The proteomic responses of the clones M and G differed at any type of stress. Clone M showed markedly stronger and less stress-specific proteomic responses than clone G, which included the consistent expression of a specific heat shock protein (HSP60) and vitellogenin (VTG-SOD).ConclusionsThe expression changes under acute stress can be interpreted as a switch from standard products of gene expression to stress-specific products. The expression changes under temperature acclimation probably served for an increase in energy intake (via digestion) and, if necessary, a decrease in energy expenditures (e.g, for translational processes). The stronger and less stress-specific proteomic responses of clone M indicate a lower degree of cell damage and an active preservation of the energy balance, which allowed adequate proteomic responses under stress, including the initiation of resting egg production (VTG-SOD expression) as an emergency reaction.

Physiological Regulation of Brown Adipose Tissue with Obesity by Mild‐Cold Exposure, a β3‐Agonist and Exercise Training at Thermoneutrality

Background and aimTherapeutic activation of thermogenic brown adipose tissue (BAT) is a potential strategy to prevent obesity and metabolic disease in humans. However, it is now recognised that rodent studies examining BAT physiology are carried out at sub‐thermoneutral temperatures (e.g. ~20°C), and are not translationally relevant to humans as BAT is ‘hyperactive’. Therefore, the aim of this study was to determine the effect of common regulators of BAT metabolism when animals were raised at thermoneutrality (28°C).Material and methodsThirty weanling Sprague‐Dawley rats were housed at thermoneutrality (28°C) and randomised to either chow (C, n=6) or a high‐fat diet (HFD, n=24) from 3‐weeks of age. At 12 weeks, subgroups (n=6) of HFD were randomised to either mild‐cold exposure (20°C), Mirabegron, a selective β3‐agonist (0.75 mk/kg/d) or exercise training (1h/d, 5 d/week). Metabolic assessment was undertaken in CLAMS during the last 48h to assess energy intake (EI), expenditure (EE) and physical activity (PA) in addition to the acute response to administration of Mirabegron. Key thermogenic and metabolic genes were analysed in interscapular BAT by qPCR in addition to targeted insulin resistance PCR Arrays (86 key genes, n=3).ResultsNo interventions reduced body weight or fat mass. Intriguingly however, mild‐cold exposure significantly increased weight‐gain during the 4‐week period (78.6 vs. 119.8g). This was accompanied by a significant increase in inguinal AT (7.14 vs 16.14g) in cold‐exposed animals whilst BAT mass was significantly increased with exercise‐training (0.74 vs. 1.2g). There was no difference in 24h EE, EI or PA between groups. Key thermogenic genes in BAT were unchanged by the interventions. CITED1 expression was upregulated by HFD and reduced by all interventions whilst PRDM16 expression was reduced by HFD and increased by exercise. Similarly, expression of PPARA, mTOR and the ‘beige’ marker TBX1 were upregulated by exercise only. Targeted PCR arrays demonstrated an upregulation of inflammatory markers e.g. TLR4, EMR1, CASP1 and IL18R1 and a downregulation of metabolic genes e.g. SCD1, FASN, ACACB, HK2 with HFD. β3 increased FASN, whilst IL18R1, IL6 and STAT3 were downregulated along with IRS2, LEP, ADIPOR1, INSR and PIK3R1. Exercise upregulated FASN, SCD1, HK, ACACA, ACACB and PDK2 but NLRP3, IL1β, PYCARD, LPL, IRS2, INSR, FABP4 and CD36 were all downregulated.ConclusionWe show there is no consistent upregulation of BAT as determined by key thermogenic genes in response to common stimuli when examined at thermoneutrality. Effects of interventions on BAT carried out at sub‐thermoneutrality are most likely to be a consequence of chronic mild‐cold stress and are unlikely to be translated to humans.Support or Funding InformationBritish Heart FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Agr Quorum Sensing System Represses Persister Formation through Regulation of Phenol Soluble Modulins in Staphylococcus aureus.

The opportunistic pathogen Staphylococcus aureus has become an increasing threat to public health. While the Agr quorum sensing (QS) system is a master regulator of S. aureus virulence, its dysfunction has been frequently reported to promote bacteremia and mortality in clinical infections. Here we show that the Agr system is involved in persister formation in S. aureus. Mutation of either agrCA or agrD but not RNAIII resulted in increased persister formation of stationary phase cultures. RNA-seq analysis showed that in stationary phase AgrCA/AgrD and RNAIII mutants showed consistent up-regulation of virulence associated genes (lip and splE, etc.) and down-regulation of metabolism genes (bioA and nanK, etc.). Meanwhile, though knockout of agrCA or agrD strongly repressed expression of phenol soluble modulin encoding genes psmα1-4, psmβ1-2 and phenol soluble modulins (PSM) transporter encoding genes in the pmt operon, mutation of RNAIII enhanced expression of the genes. We further found that knockout of psmα1-4 or psmβ1-2 augmented persister formation and that co-overexpression of PSMαs and PSMβs reversed the effects of AgrCA mutation on persister formation. We also detected the effects on persister formation by mutations of metabolism genes (arcA, hutU, narG, nanK, etc.) that are potentially regulated by Agr system. It was found that deletion of the ManNAc kinase encoding gene nanK decreased persister formation. Taken together, these results shed new light on the PSM dependent regulatory role of Agr system in persister formation and may have implications for clinical treatment of MRSA persistent infections.

Phosphorylation of the Twist1-Family Basic Helix-Loop-Helix Transcription Factors Is Involved in Pathological Cardiac Remodeling

BackgroundThe Twist1-family basic helix-loop-helix (bHLH) transcription factors including Twist1, Hand1 and Hand2, play an essential role in heart development and are implicated in pathological heart remodeling. Previously, it was reported that these bHLH transcription factors can be regulated by phosphorylation within the basic-helix I domain, which is involved in developmental processes such as limb formation and trophoblast differentiation. However, how phosphorylation of Twist1 family functions in post-natal heart is elusive.Principal FindingsHere, we generated transgenic mice with over-expression of Hand1 and Twist1 mutants (to mimic or to abolish phosphorylation) in cardiomyocytes and found pathological cardiac remodeling leading to heart failure and sudden death. Gene expression profile analysis revealed up-regulation of growth-promoting genes and down-regulation of metabolic genes. It is well known that aberrant activation of Akt signaling causes pathological cardiac remodeling and results in heart failure. The basic-helix I domain of Twist1 family members contain Akt substrate consensus motif and may be downstream targets of Akt signaling. Using biochemical analysis, we demonstrated that Hand1 and Twist1 were phosphorylated by Akt in the basic-helix I domain. Phosphorylation of Hand1 regulated its transcriptional activation of luciferase reporter genes and DNA binding ability.ConclusionsThis study provides novel insights into the regulation of Twist1 family in cardiac remodeling and suggests that the Twist1 family can be regulated by Akt signaling.

Integrated Profiling of MicroRNAs and mRNAs: MicroRNAs Located on Xq27.3 Associate with Clear Cell Renal Cell Carcinoma

BackgroundWith the advent of second-generation sequencing, the expression of gene transcripts can be digitally measured with high accuracy. The purpose of this study was to systematically profile the expression of both mRNA and miRNA genes in clear cell renal cell carcinoma (ccRCC) using massively parallel sequencing technology.MethodologyThe expression of mRNAs and miRNAs were analyzed in tumor tissues and matched normal adjacent tissues obtained from 10 ccRCC patients without distant metastases. In a prevalence screen, some of the most interesting results were validated in a large cohort of ccRCC patients.Principal FindingsA total of 404 miRNAs and 9,799 mRNAs were detected to be differentially expressed in the 10 ccRCC patients. We also identified 56 novel miRNA candidates in at least two samples. In addition to confirming that canonical cancer genes and miRNAs (including VEGFA, DUSP9 and ERBB4; miR-210, miR-184 and miR-206) play pivotal roles in ccRCC development, promising novel candidates (such as PNCK and miR-122) without previous annotation in ccRCC carcinogenesis were also discovered in this study. Pathways controlling cell fates (e.g., cell cycle and apoptosis pathways) and cell communication (e.g., focal adhesion and ECM-receptor interaction) were found to be significantly more likely to be disrupted in ccRCC. Additionally, the results of the prevalence screen revealed that the expression of a miRNA gene cluster located on Xq27.3 was consistently downregulated in at least 76.7% of ∼50 ccRCC patients.ConclusionsOur study provided a two-dimensional map of the mRNA and miRNA expression profiles of ccRCC using deep sequencing technology. Our results indicate that the phenotypic status of ccRCC is characterized by a loss of normal renal function, downregulation of metabolic genes, and upregulation of many signal transduction genes in key pathways. Furthermore, it can be concluded that downregulation of miRNA genes clustered on Xq27.3 is associated with ccRCC.

Sex-specific pathways in early cardiac response to pressure overload in mice

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (α-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFβ2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-008-0385-4) contains supplementary material, which is available to authorized users.

Inactivation of peroxisome proliferator-activated receptor isoforms α, β/δ, and γ mediate distinct facets of hypertrophic transformation of adult cardiac myocytes

Inactivation of peroxisome proliferator-activated receptor (PPARs) isoforms alpha, beta/delta, and gamma mediate distinct facets of hypertrophic transformation of adult cardiac myocytes. PPARs are ligand-activated transcription factors that modulate the transcriptional regulation of fatty acid metabolism and the hypertrophic response in neonatal cardiac myocytes. The purpose of this study was to determine the role of PPAR isoforms in the morphologic and metabolic phenotype transformation of adult cardiac myocytes in culture, which, in medium containing 20% fetal calf serum, undergo hypertrophy-like cell growth associated with downregulation of regulatory proteins of fatty acid metabolism. Expression and DNA-binding activity of PPARalpha, PPARbeta/delta, and PPARgamma rapidly decreased after cell isolation and remained persistently reduced during the 14-day culture period. Cells progressively increased in size and developed both re-expression of atrial natriuretic factor and downregulation of regulatory proteins of fatty acid metabolism. Supplementation of the medium with fatty acid (oleate 0.25 mM/palmitate 0.25 mM) prevented inactivation of PPARs and downregulation of metabolic genes. Furthermore, cell size and markers of hypertrophy were markedly reduced. Selective activation of either PPARalpha or PPARbeta/delta completely restored expression of regulatory genes of fatty acid metabolism but did not influence cardiac myocyte size and markers of hypertrophy. Conversely, activation of PPARgamma prevented cardiomyocyte hypertrophy but had no effect on fatty acid metabolism. The results indicate that PPAR activity markedly influences hypertrophic transformation of adult rat cardiac myocytes. Inactivation of PPARalpha and PPARbeta/delta accounts for downregulation of the fatty acid oxidation pathway, whereas inactivation of PPARgamma enables development of hypertrophy.