Master Regulator Of Lipid Metabolism Research Articles

Abstract 4422: Metabolic adaptations of glioblastoma in hypoxia is mediated by acox-1

Abstract Background: Glioblastoma (GBM) is a recurrent, chemoresistant, malignant brain tumor. Hypoxia is a major factor contributing to resistance in GBM which develops due to aggressive tumor growth and chronic anti-angiogenic therapy. Thus, under limited oxygen supply it is unlikely that the high energy consuming pathways are solely able to provide the energy requirement of GBM cells. Thus, based on our metabolomics data stated below we hypothesize that GBM cells adapt to chronic hypoxia utilizing alternate metabolic pathways such as peroxisomal fatty acid oxidation (FAO). Here we have explored the role of Acyl coenzyme A oxidase (ACOX-1), a rate limiting enzyme for peroxisomal FAO in the metabolic adaptations to hypoxia and as a potential drug target. Methods: U251 CRISPR dox inducible ACOX1 (KO) cells and patient derived primary GBM were grown under normoxic and hypoxic conditions (2%O2, 5%CO2, 70% humidity). Metabolic analysis was done using UHPLC-MS and LCMS analysis. RNAseq was done using TopHat2 (genome alignment), HTSeq, and DEseq to study the differential gene expression at cut-off of 2-fold change, and p<0.05. GSEA was used to interpret biological pathways. NCr/SCID (Severe Combined Immunodeficiency) mice (n=5) inoculated with U251 ACOX1 knockout cells expressing luciferase were used and treated with anti-angiogenic agent pazopanib at 30 mg/kg, 5 days a week. The U251 luciferase-labeled tumors were imaged starting weekly for tumor volumes using the IVIS (In Vivo Imaging System) Lumina. Results: In patient derived primary GBM cell lines alterations in metabolites in chronic hypoxia compared to normoxia, such as decrease in citric acid cycle metabolites, increase in glycolytic metabolites, and dysfunctional mitochondrial metabolites. In RNA seq downregulation of genes PCK1, SCD, SREBF1, and PIPOX (p<1x108) involved in PPAR and lipid metabolism pathways in hypoxia versus normoxia were noted. Inhibition of ACOX-1 displayed increased survival in mice administered (p=6.7E-04) with pazopanib compared to the U251 parental control group. Conclusion: There is metabolomic reprogramming in ACOX-1 KO cells channeled predominantly through FAO as seen through the downregulation of genes downstream of the PPAR signaling pathway, mediated through SREBF1 the master regulator of lipid metabolism. Thus, these genes could be future targets for therapy in combination with anti-angiogenic therapies that aggravate hypoxia in GBM. Citation Format: Ayon Bhattacharya, Laura Caflisch, Henriette Balinda, Alessia Lodi, Mei Zhou, Mengxing Li, Jennifer Chiou, Renu Pandey, Gangadhara R. Sareddy, Stefano Tiziani, Yidong Chen, Ratna K. Vadlamudi, Andrew J. Brenner. Metabolic adaptations of glioblastoma in hypoxia is mediated by acox-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4422.

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery.

Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator-activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout (MBKO) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.

Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice

Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.

371 Activated PPARβ/QKI Signaling in Macrophage/Microglia Sensitizes Glioblastoma to Immunotherapy

INTRODUCTION: Glioblastomas (GBMs) share overwhelmingly immunosuppressive tumor microenvironments that are enriched in glioblastoma-associated macrophages and microglia (GAMs). Notably, GAMs have distinctive reshuffling of lipid composition and dysfunctional lipid metabolism. The peroxisome proliferator-activated receptor (PPAR) family members are master regulators of lipid metabolism in macrophages. One of the PPARs, PPARβ is a pivotal modulator of lipid metabolism in macrophages that orchestrates timely disposal of GBM cells. METHODS: Co-immunoprecipitation using an anti-Qki antibody was followed by detecting PPARβ. PPARβ and QKI levels were compared between GAMs inside GBMs and paired macrophages/microglia outside GBMs, as well as human low-grade versus high-grade gliomas. Survival was collected from CX3CR1-CreERT2; PpardL/L/Qki+/+ mice (PPARβ KO) (Ppard is the gene name for PPARβ), CX3CR1-CreERT2; Ppard+/+/QkiL/L mice (QKI KO) and control CX3CR1-CreERT2; Ppard+/+/Qki+/+ (Ctrl) mice given tamoxifen when implanted with GL261 cells. Survival was collected for GBM bearing mice given PPARβ agonist, KD3010 and/or anti-PD-1 therapy. RESULTS: PPARβ co-activates the QKI-mediated complex, which is an essential mediator of phagocytosis in macrophage/microglia. Moreover, PPARβ/QKI signaling is markedly decreased in GAMs relative to paired macrophages/microglia within boundary brain parenchyma (P < 0.001). Myeloid cell–specific PPARβ; or QKI knockout shorten overall survival of GBM–bearing mice (P < 0.05), and inhibited PPARβ/QKI signaling in GAMs correlates with grade progression in human gliomas (P < 0.01) and worse prognosis for GBM (P = 0.0034). Therapeutically, PPARβ agonist plus anti-PD-1 greatly prolongs survival of mice GBMs relative to anti-PD-1 monotherapy (P < 0.05). CONCLUSIONS: We characterize dysfunctional lipid metabolism in GAMs and elucidates the mechanism underlying immunosuppression of GAMs caused by PPARβ/QKI loss. The study supports for therapeutic options for restoring PPARβ/QKI-mediated lipid metabolism in GAMs and development of novel strategies to sensitize GBM to immunotherapy.

Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options.

During the last decade, the understanding of the biological functions of cholesterol biosynthesis intermediates has changed significantly. Particularly, the enzyme sterol dehydrocholesterol reductase 24 (DHCR24) has taken center stage as a potential drug target. Inhibition of DHCR24 leads to accumulation of the endogenous, biologically active metabolite cholesta-5,24-dien-3β-ol (desmosterol). Desmosterol is an endogenous agonist of the liver X receptor (LXR). LXR is a master regulator of lipid metabolism and, as such, is involved in numerous pathophysiological processes such as inflammation, atherosclerosis, cancer, diabetes mellitus (DM), multiple sclerosis (MS), nonalcoholic steatohepatitis (NASH), and the progression of viral infections. Up to now, selective pharmacological targeting of LXR without activating the sterol-response element binding proteins (SREBP) and thereby boosting endogenous lipid biosynthesis has not been achieved. In turn, no selective LXR receptor agonists leveraging its beneficial activation have yet reached the clinic. Therefore, using potent and selective inhibitors of DHCR24 leading to an accumulation of endogenous desmosterol is a promising alternative strategy for the selective activation of LXR. Here we summarize the present landscape of novel lead structures for targeting DHCR24, covering steroidal enzyme inhibitors (e.g., 20,25-diazacholesterol, SH42) as well as nonsteroidal scaffolds (e.g., amiodarone, triparanol). Further, we explain the molecular mechanisms of DHCR24 inhibition/LXR activation, discuss possible therapeutic applications, and underpin why DHCR24 is an upcoming promising drug target.

Leptin Silencing Attenuates Lipid Accumulation through Sterol Regulatory Element-Binding Protein 1 Inhibition in Nasopharyngeal Carcinoma.

Leptin is a crucial regulator of metabolism and energy homeostasis in mammals. Many studies have investigated the impacts of leptin on human cancers, such as proliferation and metastasis. However, the mechanisms underlying leptin-mediated regulation of lipid metabolism in nasopharyngeal carcinoma (NPC) remain incompletely understood. In the current study, leptin downregulation ameliorated lipid accumulation, triglyceride, and cholesterol levels. Mechanistically, diminished leptin by siRNA not only inhibited sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipid metabolism, at the mRNA and protein levels, but also reduced SREBP1 downstream target expressions, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1), in NPC cells. In addition, leptin expression could modulate the promoter activity of SREBP1. We also found that pharmacological inhibition of poly-ADP ribose polymerase-γ (PPAR-γ) resulted in increased SREBP1 expression in leptin-depleted NPC cells. Functionally, SREBP1 overexpression overcame the effects of leptin-silencing attenuated triglyceride level, cholesterol level and cell survival in NPC cells. Taken together, our results demonstrate that leptin is an important regulator of lipid metabolism in NPC cells and might could be a potential therapeutic target for treatment of NPC patients.

SREBP1 regulates Lgals3 activation in response to cholesterol loading

Aberrant smooth muscle cell (SMC) plasticity is etiological to vascular diseases. Cholesterol induces SMC phenotypic transition featuring high LGALS3 (galectin-3) expression. This proatherogenic process is poorly understood for its molecular underpinnings, in particular, the mechanistic role of sterol regulatory-element binding protein-1 (SREBP1), a master regulator of lipid metabolism. Herein we show that cholesterol loading stimulated SREBP1 expression in mouse, rat, and human SMCs. SREBP1 positively regulated LGALS3 expression (and vice versa), whereas Krüppel-like factor-15 (KLF15) acted as a negative regulator. Both bound to the Lgals3 promoter, yet at discrete sites, as revealed by chromatin immunoprecipitation-qPCR and electrophoretic mobility shift assays. SREBP1 and LGALS3 each abated KLF15 protein, and blocking the bromo/extraterminal domain-containing proteins (BETs) family of acetyl-histone readers abolished cholesterol-stimulated SREBP1/LGALS3 protein production. Furthermore, silencing bromodomain protein 2 (BRD2; but not other BETs) reduced SREBP1; endogenous BRD2 co-immunoprecipitated with SREBP1’s transcription-active domain, its own promoter DNA, and that of Lgals3. Thus, results identify a previously uncharacterized cholesterol-responsive dyad—SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition. This study provides new insights into SMC phenotypic transition and potential interventional targets.

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma.

Simple SummaryClear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional systemic therapies and also known for abnormal lipid accumulation. Identifying the actors and deciphering the molecular mechanisms that lead to tumor progression is an important step in the development of new therapeutic strategies to cure ccRCC. In this context, we focused our attention on miR-21, an oncogenic miRNA upregulated in many solid tumors, and peroxysome proliferator-activated receptor-α (PPAR- α), the master regulator of lipid metabolism and one target of miR-21. In this study, our data show a double-negative feedback interaction between PPAR-α and miR-21. Thus, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

Sex Differences in Nonalcoholic Fatty Liver Disease: Estrogen Influence on the Liver-Adipose Tissue Crosstalk.

Significance: Nonalcoholic fatty liver disease (NAFLD) is a hepatic and systemic disorder with a complex multifactorial pathogenesis. Owing to the rising incidence of obesity and diabetes mellitus, the prevalence of NAFLD and its impact on global health care are expected to increase in the future. Differences in NAFLD exist between males and females, and among females depending on their reproductive status. Clinical and preclinical data show that females in the fertile age are more protected against NAFLD, and studies in postmenopausal women and ovariectomized animal models support a protective role for estrogens. Recent Advances: An efficient crosstalk between the liver and adipose tissue is necessary to regulate lipid and glucose metabolism, protecting the liver from steatosis and insulin resistance contributing to NALFD. New advances in the knowledge of sexual dimorphism in liver and adipose tissue are providing interesting clues about the sex differences in NAFLD pathogenesis that could inspire new therapeutic strategies. Critical Issues: Sex hormones influence key master regulators of lipid metabolism and oxidative stress in liver and adipose tissue. All these sex-biased metabolic adjustments shape the crosstalk between liver and adipose tissue, contributing to the higher protection of females to NAFLD. Future Directions: The development of novel drugs based on the protective action of estrogens, but without its feminizing or undesired side effects, might provide new therapeutic strategies for the management of NAFLD. Antioxid. Redox Signal. 35, 753-774.

Not So Slim Anymore-Evidence for the Role of SUMO in the Regulation of Lipid Metabolism.

One of the basic building blocks of all life forms are lipids—biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions and functions of lipids with the physiology of the organism. One type of control on the activity of those enzymes is the conjugation of the Small Ubiquitin-like Modifier (SUMO) that in recent years has been identified as a critical regulator of many biological processes. In this review, I summarize the current knowledge about the role of SUMO in the regulation of lipid metabolism. In particular, I discuss (i) the role of SUMO in lipid metabolism of fungi and invertebrates; (ii) the function of SUMO as a regulator of lipid metabolism in mammals with emphasis on the two most well-characterized cases of SUMO regulation of lipid homeostasis. These include the effect of SUMO on the activity of two groups of master regulators of lipid metabolism—the Sterol Regulatory Element Binding Protein (SERBP) proteins and the family of nuclear receptors—and (iii) the role of SUMO as a regulator of lipid metabolism in arteriosclerosis, nonalcoholic fatty liver, cholestasis, and other lipid-related human diseases.

180-OR: Tissue-Specific Functions of PPARα Overexpression in Liver, Adipose, and Pancreatic ß Cells

Peroxisome proliferator-activated receptor (PPAR) α is one of the master regulators of lipid metabolism and the major target of fibrates, a class of drugs improving dyslipidemia in metabolic syndromes. To understand the tissue-specific roles of PPARα and the coordination among multiple organs, we employed newly generated mouse models enabling doxycycline-inducible overexpression of PPARα specifically in liver, adipose or the insulin-producing pancreatic β-cells. Titrated by doxycycline dose, a moderate elevation of PPARα proteins in liver activated the transcription of its target genes. In mice with diet-induced obesity, hepatic overexpression of PPARα significantly reduced steatosis and improved systemic insulin sensitivity. Surprisingly, systemic triglyceride clearance was dramatically impaired, associated with a trend towards faster VLDL secretion. PPARα overexpression in adipose tissues had a marginal effect on systemic insulin sensitivity. However, inflammation was markedly ameliorated in white but not brown fat pads. Pancreatic β-cell-specific overexpression of PPARα resulted in a significant decrease in glucose-stimulated insulin secretion, suggesting a negative impact of PPARα induction on β-cell function. Taken together, our findings reveal the differential actions of enhanced PPARα on local tissues and whole-body metabolism and call for caution to the potential adverse effects from fibrate treatment. Further dissection of PPARα signaling with our mouse models may facilitate the discovery of novel therapeutic targets with high efficacy and specificity. Disclosure R. Ye: None. P.E. Scherer: None. Funding National Institutes of Health (R01DK55758, R01DK099110, P01-DK088761-01); JDRF (17-2012-36); Novo Nordisk Foundation (to P.E.S.)

ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis

Tubulointerstitial fibrosis is a strong predictor of progression in patients with chronic kidney disease, and is often accompanied by lipid accumulation in renal tubules. However, the molecular mechanisms modulating the relationship between lipotoxicity and tubulointerstitial fibrosis remain obscure. ATF6α, a transcription factor of the unfolded protein response, is reported to be an upstream regulator of fatty acid metabolism. Owing to their high energy demand, proximal tubular cells (PTCs) use fatty acids as their main energy source. We therefore hypothesized that ATF6α regulates PTC fatty acid metabolism, contributing to lipotoxicity-induced tubulointerstitial fibrosis. Overexpression of activated ATF6α transcriptionally downregulated peroxisome proliferator-activated receptor-α (PPARα), the master regulator of lipid metabolism, leading to reduced activity of fatty acid β-oxidation and cytosolic accumulation of lipid droplets in a human PTC line (HK-2). ATF6α-induced lipid accumulation caused mitochondrial dysfunction, enhanced apoptosis, and increased expression of connective tissue growth factor (CTGF), as well as reduced cell viability. Atf6α-/- mice had sustained expression of PPARα and less tubular lipid accumulation following unilateral ischemia-reperfusion injury (uIRI), resulting in the amelioration of apoptosis; reduced expression of CTGF, α-smooth muscle actin, and collagen I; and less tubulointerstitial fibrosis. Administration of fenofibrate, a PPARα agonist, reduced lipid accumulation and tubulointerstitial fibrosis in the uIRI model. Taken together, these findings suggest that ATF6α deranges fatty acid metabolism in PTCs, which leads to lipotoxicity-mediated apoptosis and CTGF upregulation, both of which promote tubulointerstitial fibrosis.

Direct Activation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by PF-06409577 Inhibits Flavivirus Infection through Modification of Host Cell Lipid Metabolism.

Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of AMP-activated protein kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses, namely, West Nile virus (WNV), Zika virus (ZIKV), and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis, affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barré syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease, which can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced WNV, ZIKV, and DENV infection. This antiviral effect was associated with an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery.

Brg1 regulates pro-lipogenic transcription by modulating SREBP activity in hepatocytes

Alteration of hepatic lipid metabolism contributes to a range of human diseases including steatosis. Sterol response element binding protein (SREBP) is the master regulator of lipid metabolism. The epigenetic mechanism whereby SREBP activity is regulated remains incompletely understood. We have previously shown that systemic knockdown of brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuates steatosis in mice by down-regulating the synthesis of pro-inflammatory mediators. Here we show that hepatocyte conditional Brg1 knockout (HepcKO) mice were largely protected from high-fat diet (HFD) induced steatosis as evidenced by decelerated weight gains, improved insulin sensitivity, ameliorated steatotic injuries, and diminished hepatic inflammation. Brg1 contributed to lipid metabolism by trans-activating the genes involved in fatty acid esterification. Mechanistically, Brg1 interacted with and was recruited by sterol response element binding protein (SREBP1c) to the promoters of SREBP target genes and optimized the chromatin structure to facilitate SREBP1c binding. Therefore, our data have identified a previously unrecognized role for Brg1 in hepatic lipid metabolism by portraying Brg1 as an essential epigenetic co-factor for SREBP1c.

Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan

Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.

Aberrant lipid metabolism in cancer cells - the role of oncolipid-activated signaling.

Metabolic activity of malignant cells is very different from that of their nontransformed equivalents, which establishes metabolic reprogramming as an important hallmark of every transformed cell. In particular, the current arena of research in this field aims to understand the regulatory effect of oncogenic signaling on metabolic rewiring in transformed cells in order to exploit this for therapeutic benefit. Alterations in lipid metabolism are one of the main aspects of metabolic rewiring of transformed cells. Up-regulation ofseveral lipogenic enzymes has been reported to be a characteristic of various cancer types. Lysophosphatidic acid (LPA), a simple byproduct of the lipid biosynthesis pathway, has gained immense importance due to its elevated level in several cancers and associated growth-promoting activity. Importantly, a current study revealed its role in increased denovo lipid synthesis through up-regulation of sterol regulatory element-binding protein 1, a master regulator of lipid metabolism. This review summarizes the recent insights in the field of oncolipid LPA-mediated signaling in regard to lipid metabolism in cancers. Future work in this domain is required to understand the up-regulation of the denovo synthesis pathway and the role of its end products in malignant cells. This will open a new arena of research toward the development of specific metabolic inhibitors that can add to the pre-existing chemotherapeutics in order to increase the efficacy of clinical output in cancer patients.

PPAR-α, a lipid-sensing transcription factor, regulates blood–brain barrier efflux transporter expression

Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR-α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood–brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR-α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR-α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood–brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.

Metabolomics reveal 1-palmitoyl lysophosphatidylcholine production by peroxisome proliferator-activated receptor α

PPARα is well known as a master regulator of lipid metabolism. PPARα activation enhances fatty acid oxidation and decreases the levels of circulating and cellular lipids in obese diabetic patients. Although PPARα target genes are widely known, little is known about the alteration of plasma and liver metabolites during PPARα activation. Here, we report that metabolome analysis-implicated upregulation of many plasma lysoGP species during bezafibrate (PPARα agonist) treatment. In particular, 1-palmitoyl lysophosphatidylcholine [LPC(16:0)] is increased by bezafibrate treatment in both plasma and liver. In mouse primary hepatocytes, the secretion of LPC(16:0) increased on PPARα activation, and this effect was attenuated by PPARα antagonist treatment. We demonstrated that Pla2g7 gene expression levels in the murine hepatocytes were increased by PPARα activation, and the secretion of LPC(16:0) was suppressed by Pla2g7 siRNA treatment. Interestingly, LPC(16:0) activates PPARα and induces the expression of PPARα target genes in hepatocytes. Furthermore, we showed that LPC(16:0) has the ability to recover glucose uptake in adipocytes induced insulin resistance. These results reveal that LPC(16:0) is induced by PPARα activation in hepatocytes; LPC(16:0) contributes to the upregulation of PPARα target genes in hepatocytes and the recovery of glucose uptake in insulin-resistant adipocytes.

Integrated physiology and systems biology of PPARα.

The Peroxisome Proliferator Activated Receptor alpha (PPARα) is a transcription factor that plays a major role in metabolic regulation. This review addresses the functional role of PPARα in intermediary metabolism and provides a detailed overview of metabolic genes targeted by PPARα, with a focus on liver. A distinction is made between the impact of PPARα on metabolism upon physiological, pharmacological, and nutritional activation. Low and high throughput gene expression analyses have allowed the creation of a comprehensive map illustrating the role of PPARα as master regulator of lipid metabolism via regulation of numerous genes. The map puts PPARα at the center of a regulatory hub impacting fatty acid uptake, fatty acid activation, intracellular fatty acid binding, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, triglyceride turnover, lipid droplet biology, gluconeogenesis, and bile synthesis/secretion. In addition, PPARα governs the expression of several secreted proteins that exert local and endocrine functions.

C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

The unfolded protein response (UPR) senses stress in the endoplasmic reticulum (ER) and initiates signal transduction cascades that culminate in changes to gene regulation. Long recognized as a means for improving ER protein folding through up-regulation of ER chaperones, the UPR is increasingly recognized to play a role in the regulation of metabolic pathways. ER stress is clearly connected to altered metabolism in tissues such as the liver, but the mechanisms underlying this connection are only beginning to be elucidated. Here, working exclusively in vivo, we tested the hypothesis that the UPR-regulated CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) participates in the transcriptional regulation of metabolism during hepatic ER stress. We found that metabolic dysregulation was associated with induction of eIF2α signaling and CHOP up-regulation during challenge with tunicamycin or Velcade. CHOP was necessary for suppression of genes encoding the transcriptional master regulators of lipid metabolism: Cebpa, Ppara, and Srebf1. This action of CHOP required a contemporaneous CHOP-independent stress signal. CHOP bound directly to C/EBP-binding regions in the promoters of target genes, whereas binding of C/EBPα and C/EBPβ to the same regions was diminished during ER stress. Our results thus highlight a role for CHOP in the transcriptional regulation of metabolism.