Nuclear Receptor PPARα Research Articles

Comparison of Sweated and Non-Sweated Ethanol Extracts of Salvia miltiorrhiza Bge. (Danshen) Effects on Human and Rat Hepatic UDP-Glucuronosyltransferase and Preclinic Herb-Drug Interaction Potential Evaluation.

The ethanol of Danshen (DEE) preparation has been widely used to treat cardiac-cerebral disease and cancer. Sweating is one of the primary processing methods of Danshen, which greatly influences its quality and pharmacological properties. Sweated and non-sweated DEE preparation combined with various synthetic drugs, add up the possibility of herbal-drug interactions. This study explored the effects of sweated and non-sweated DEE on human and rat hepatic UGT enzyme expression and activity and proposed a potential mechanism. The expression of two processed DEE on rat UGT1A, UGT2B, and nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor α (PPARα), were investigated after intragastric administration in rats by Western blot. Enzyme activity of DEE and its active ingredients (Tanshinone I, Cryptotanshinone, and Tanshinone I) on UGT isoenzymes was evaluated by quantifying probe substrate metabolism and metabolite formation in vitro using Ultra Performance Liquid Chromatography. The two processed DEE (5.40 g/kg) improved UGT1A (P<0.01) and UGT2B (P<0.05) protein expression, and the non-sweated DEE (2.70 g/kg) upregulated UGT2B expression protein (P<0.05), compared with the CMCNa group. On day 28, UGT1A protein expression was increased (P<0.05) both in two processed DEE groups meanwhile, the non-sweated DEE significantly enhanced UGT2B protein expression (P<0.05) on day 21, compared with the CMCNa group. The process underlying this mechanism involved the activation of nuclear receptors CAR, PXR, and PPARα. In vitro, sweated DEE (0-80 μg/mL) significantly inhibited the activity of human UGT1A7 (P<0.05) and rat UGT1A1, 1A8, and 1A9 (P<0.05). Non-sweated DEE (0-80 μg/mL) dramatically suppressed the activity of human UGT1A1, 1A3, 1A6, 1A7, 2B4, and 2B15, and rat UGT1A1, 1A3, 1A7, and 1A9 (P<0.05). Tanshinone I (0-1 μM) inhibited the activity of human UGT1A3, 1A6, and 1A7 (P<0.01) and rat UGT1A3, 1A6, 1A7, and 1A8 (P<0.05). Cryptotanshinone (0-1 μM) remarkably inhibited the activity of human UGT1A3 and 1A7 (P<0.05) and rat UGT1A7, 1A8, and 1A9 (P<0.05). Nonetheless, Tanshinone IIA (0-2 μM) is not a potent UGT inhibitor both in humans and rats. Additionally, there existed significant differences between two processed DEE in the expression of PXR, and the activity of human UGT1A1, 1A3, 1A6, and 2B15 and rat UGT1A3, and 2B15 (P<0.05). The effects of two processed DEE on hepatic UGT enzyme expression and activity differed. Accordingly, the combined usage of related UGTs substrates with DEE and its monomer components preparations may call for caution, depending on the drug's exposure-response relationship and dose adjustment. Besides, it is vital to pay attention to the distinction between sweated and non-sweated Danshen in clinic, which influences its pharmacological activity.

Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH.

Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities.

Bempedoic acid as a PPARα activator: New perspectives for hepatic steatosis treatment in a female rat experimental model

IntroductionIn its initial stages, nonalcoholic fatty liver disease presents hypertriglyceridemia and accumulation of lipids in the liver (hepatic steatosis). Bempedoic acid is an ATP:citrate lyase inhibitor that promotes a dual inhibition of the synthesis of cholesterol and fatty acids. However, its effect in the prevention/treatment of hepatic steatosis and hypertriglyceridemia has not been investigated. The aim of our work has been to elucidate whether bempedoic acid, through a mechanism other than ATP:citrate lyase inhibition, reverses these metabolic alterations. Experimental designThe study was carried out in female Sprague-Dawley rats fed, for three months, with a high fat diet supplemented with fructose (10% w/v) in drinking water. During the last month, bempedoic acid (30 mg/kg/day) was administered to a group of animals. Zoometric and plasmatic parameters were analyzed, gene and protein expression analysis were performed in liver samples and PPAR-PPRE binding activity was determined. ResultsOur interventional model developed hepatic steatosis and hypertriglyceridemia. Despite an increase in total caloric intake, there was no increase in body weight of the animals. The administration of bempedoic acid significantly reduced hepatic steatosis and promoted a marked hepatocyte hypertrophy. There was a 66% increase in the liver weight of the animals treated with the drug that was not accompanied by modifications in the markers of inflammation, oxidative stress, or endoplasmic reticulum stress. Bempedoic acid activated the peroxisome proliferator activated nuclear receptor (PPARα) and its target genes. ConclusionsBempedoic acid could be an effective therapy for the treatment of fatty liver and associated cardiovascular risk. Bempedoic acid has other mechanisms of action besides the inhibition of ATP:citrate lyase, such as the activation of PPARα, which could explain the reduction in hepatic steatosis and the increase in liver weight observed in animals treated with the drug.

Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue.

The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for β-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) with HFD, compared to control littermates. No changes in adiposity were observed in female mice compared to control littermates. In the males, the loss of PPARα signaling in adipocytes caused significantly higher cholesterol esters, activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1), and a shift in macrophage polarity from M2 to M1 macrophages. We found that the loss of adipocyte PPARα caused significantly higher expression of the Per-Arnt-Sim kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK–SREBP-1 axis significantly increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). The loss of adipocyte PPARα increased Nos2 in the males, an M1 macrophage marker indicating that the population of macrophages had changed to proinflammatory. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis, inflammation, and cholesterol ester accumulation that leads to adipocyte tissue expansion in obesity.

PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α.

Background: PXR is a xenobiotic-responsive nuclear receptor that controls the expression of drug-metabolizing enzymes. Drug-induced activation of PXR sometimes causes drug–drug interactions due to the induced metabolism of co-administered drugs. Our group recently reported a possible drug–drug interaction mechanism via an interaction between the nuclear receptors CAR and PPARα. As CAR and PXR are structurally and functionally related receptors, we investigated possible crosstalk between PXR and PPARα. Methods: Human hepatocyte-like HepaRG cells were treated with various PXR ligands, and mRNA levels were determined by quantitative reverse transcription PCR. Reporter assays using the HMGCS2 promoter containing a PPARα-binding motif and mammalian two-hybrid assays were performed in HepG2 or COS-1 cells. Results: Treatment with PXR activators reduced the mRNA levels of PPARα target genes in HepaRG cells. In reporter assays, PXR suppressed PPARα-dependent gene expression in HepG2 cells. In COS-1 cells, co-expression of PGC1α, a common coactivator of PPARα and PXR, enhanced PPARα-dependent gene transcription, which was clearly suppressed by PXR. Consistently, in mammalian two-hybrid assays, the interaction between PGC1α and PPARα was attenuated by ligand-activated PXR. Conclusion: The present results suggest that ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting PGC1α recruitment.

El ácido bempedoico como activador PPARα: Nuevas perspectivas para el tratamiento de la esteatosis hepática en un modelo experimental de rata hembra

IntroductionIn its initial stages, nonalcoholic fatty liver disease presents hypertriglyceridemia and accumulation of lipids in the liver (hepatic steatosis). Bempedoic acid is an ATP:citrate lyase inhibitor that promotes a dual inhibition of the synthesis of cholesterol and fatty acids. However, its effect in the prevention / treatment of hepatic steatosis and hypertriglyceridemia has not been investigated. The aim of our work has been to elucidate whether bempedoic acid, through a mechanism other than ATP:citrate lyase inhibition, reverses these metabolic alterations. Experimental designThe study was carried out in female Sprague-Dawley rats fed, for three months, with a high fat diet supplemented with fructose (10% w/v) in drinking water. During the last month, bempedoic acid (30mg/kg/day) was administered to a group of animals. Zoometric and plasmatic parameters were analyzed, gene and protein expression analysis were performed in liver samples and PPAR-PPRE binding activity was determined. ResultsOur interventional model developed hepatic steatosis and hypertriglyceridemia. Despite an increase in total caloric intake, there was no increase in body weight of the animals. The administration of bempedoic acid significantly reduced hepatic steatosis and promoted a marked hepatocyte hypertrophy. There was a 66% increase in the liver weight of the animals treated with the drug that was not accompanied by modifications in the markers of inflammation, oxidative stress, or endoplasmic reticulum stress. Bempedoic acid activated the peroxisome proliferator activated nuclear receptor (PPARα) and its target genes. ConclusionsBempedoic acid could be an effective therapy for the treatment of fatty liver and associated cardiovascular risk. Bempedoic acid has other mechanisms of action besides the inhibition of ATP: citrate lyase, such as the activation of PPARα, which could explain the reduction in hepatic steatosis and the increase in liver weight observed in animals treated with the drug.

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

SummaryMesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumors displayed a transcriptional signature consistent with increased activity of nuclear receptors PPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

PPARα Modulation-Based Therapy in Central Nervous System Diseases

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

Dietary Conjugated Linoleic Acid Modulates the Hepatic Circadian Clock Program via PPARα/REV-ERBα-Mediated Chromatin Modification in Mice.

Scope: Disruptions of circadian rhythm cause metabolic disorders and are closely related to dietary factors. In this study, we investigated the interplays between the dietary conjugated linoleic acid (CLA)-induced hepatic steatosis and the circadian clock regulation, in association with lipid homeostasis.Methods and Results: Exposure of mice to 1.5% dietary CLA for 28 days caused insulin resistance, enlarged livers, caused hepatic steatosis, and increased triglyceride levels. Transcriptional profiling showed that hepatic circadian clock genes were significantly downregulated with increased expression of the negative transcription factor, REV-ERBα. We uncovered that the nuclear receptor (NR) PPARα, as a major target of dietary CLA, drives REV-ERBα expression via its binding to key genes of the circadian clock, including Cry1 and Clock, and the recruitment of histone marks and cofactors. The PPARα or REV-ERBα inhibition blocked the physical connection of this NR pair, reduced the cobinding of PPARα and REV-ERBα to the genomic DNA response element, and abolished histone modifications in the CLA-hepatocytes. In addition, we demonstrated that CLA promotes PPARα driving REV-ERBα transcriptional activity by directly binding to the PPAR response element (PPRE) at the Nr1d1 gene.Conclusions: Our results add a layer to the understanding of the peripheral clock feedback loop, which involves the PPARα-REV-ERBα, and provide guidance for nutrients optimization in circadian physiology.

Maternal high-fat diet during pregnancy with concurrent phthalate exposure leads\xa0to abnormal placentation

Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical commonly used for its plasticizing capabilities. Because of the extensive production and use of DEHP, humans are exposed to this chemical daily. Diet is a significant exposure pathway and fatty food contain the highest level of phthalates. The impact on pregnancy following DEHP exposure and the associated interaction of high fat (HF) diet remains unknown. Here we report that exposure of pregnant mice to an environmentally relevant level of DEHP did not affect pregnancy. In contrast, mice fed a HF diet during gestation and exposed to the same level of DEHP display marked impairment in placental development, resulting in poor pregnancy outcomes. Our study further reveals that DEHP exposure combined with a HF diet interfere with the signaling pathway controlled by nuclear receptor PPARγ to adversely affect differentiation of trophoblast cells, leading to compromised vascularization and glucose transport in the placenta. Collectively, these findings demonstrate that maternal diet during pregnancy is a critical factor that determines whether exposure to an environmental toxicant results in impaired placental and fetal development, causing intrauterine growth restriction, fetal morbidity, and mortality.

PPARα in Osteocytes Regulates Marrow Fat

The nuclear receptor PPARα is known as a major regulator of lipid metabolism and a pharmacologic target to treat dyslipidemia. However, PPARα role in maintenance of bone mass and bone marrow adipose tissue (BMAT) has not been studied in detail. Previously, we observed that mice with global deletion of PPARα (αKO) have increased BMAT volume and altered bone phenotype. Primary osteocytes isolated from αKO showed 1488 differentially expressed transcripts in Next Generation Sequencing analysis. Interestingly, we found that genes related to osteogenesis, differentiation and secreted proteins were down-regulated while apoptotic genes were up-regulated in αKO osteocytes by DAVID functional clustering analysis. Additionally, majority of cells in bone are osteocytes, thus we hypothesized that PPARα in osteocyte plays an important role in regulation of bone structure and bone marrow fat (BMF) accumulation. To test this hypothesis, we developed osteocyte specific PPARα knock-out, 10kb-Dmp1CrePPARαfl/fl, mouse (αOT-KO). We observed that αOT-KO mice had significantly increased BMF volume in whole tibia. Interestingly marrow fat in the proximal tibia contributed to the increased marrow fat observed in αOT-KO mice. However, bone structure was not different compared to the controls. Likewise, conditioned media (CM) collected from primary cultures of αKO osteocytes increased expressions of adipogenic markers aP2, CD36 and LPL in recipient WT marrow mesenchymal stem cells (MSC) in co-culture experiment. In summary, PPARα deficient osteocytes release factors which support adipocyte differentiation from MSC in vitro. Thus, PPARα controls osteocyte paracrine activities controlling BMAT development, suggesting that this nuclear receptor can be a potential pharmacologic target to control BMAT accumulation.

Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease causing serious liver complications, including nonalcoholic steatohepatitis (NASH). Nuclear receptor PPARα (peroxisome proliferator-activated receptor α) has drawn special attention recently as a potential developmental drug target to treat type-2 diabetes and related diseases due to its unique functions in regulating lipid metabolism, promoting triglyceride oxidation, and suppressing hepatic inflammation, raising interest in PPARα agonists as potential therapies for NAFLD. However, how PPARα coordinates potential treatment of NAFLD and NASH between various metabolic pathways is still obscure. Here, we show that the DY series of novel selective PPARα modulators activate PPARα by up-regulating PPARα target genes directly involved in NAFLD and NASH. The design, synthesis, docking studies, and in vitro and in vivo evaluation of the novel DY series of PPARα agonists are described.

Curcumin promotes oligodendrocyte differentiation and their protection against TNF-\u03b1 through the activation of the nuclear receptor PPAR-\u03b3

Curcumin is a compound found in the rhizome of Curcuma longa (turmeric) with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. The current study aims to assess the effects of this natural compound on oligodendrocyte progenitor (OP) differentiation, particularly in inflammatory conditions. We found that curcumin can promote the differentiation of OPs and to counteract the maturation arrest of OPs induced by TNF-α by a mechanism involving PPAR-γ (peroxisome proliferator activated receptor), a ligand-activated transcription factor with neuroprotective and anti-inflammatory capabilities. Furthermore, curcumin induces the phosphorylation of the protein kinase ERK1/2 known to regulate the transition from OPs to immature oligodendrocytes (OLs), by a mechanism only partially dependent on PPAR-γ. Curcumin is also able to raise the levels of the co-factor PGC1-α and of the cytochrome c oxidase core protein COX1, even when OPs are exposed to TNF-α, through a PPAR-γ-mediated mechanism, in line with the known ability of PPAR-γ to promote mitochondrial integrity and functions, which are crucial for OL differentiation to occur. Altogether, this study provides evidence for a further mechanism of action of curcumin besides its well-known anti-inflammatory properties and supports the suggested therapeutic potential of this nutraceutical in demyelinating diseases.

Perfluoroalkyl Acid Binding with Peroxisome Proliferator-Activated Receptors α, γ, and δ, and Fatty Acid Binding Proteins by Equilibrium Dialysis with a Comparison of Methods.

The biological impacts of per- and polyfluorinated alkyl substances (PFAS) are linked to their protein interactions. Existing research has largely focused on serum albumin and liver fatty acid binding protein, and binding affinities determined with a variety of methods show high variability. Moreover, few data exist for short-chain PFAS, though their prevalence in the environment is increasing. We used molecular dynamics (MD) to screen PFAS binding to liver and intestinal fatty acid binding proteins (L- and I-FABPs) and peroxisome proliferator activated nuclear receptors (PPAR-α, -δ and -γ) with six perfluoroalkyl carboxylates (PFCAs) and three perfluoroalkyl sulfonates (PFSAs). Equilibrium dissociation constants, KDs, were experimentally determined via equilibrium dialysis (EqD) with liquid chromatography tandem mass spectrometry for protein-PFAS pairs. A comparison was made between KDs derived from EqD, both here and in literature, and other in vitro approaches (e.g., fluorescence) from literature. EqD indicated strong binding between PPAR-δ and perfluorobutanoate (0.044 ± 0.013 µM) and perfluorohexane sulfonate (0.035 ± 0.0020 µM), and between PPAR-α and perfluorohexanoate (0.097 ± 0.070 µM). Unlike binding affinities for L-FABP, which increase with chain length, KDs for PPARs showed little chain length dependence by either MD simulation or EqD. Compared with other in vitro approaches, EqD-based KDs consistently indicated higher affinity across different proteins. This is the first study to report PPARs binding with short-chain PFAS with KDs in the sub-micromolar range.

Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH.

Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.

Влияние адипонектина на продукцию аполипопротеинов А-1 и Е макрофагами человека

Adiponectin is an adipose tissue hormone affecting energy and lipoprotein metabolism and modulating inflammatory responses. However, the role of this adipokine in atherogenesis remains poorly understood. The aim of this study was to investigate the effect of adiponectin on the production of apolipoproteins (apo) A-l and E by human macrophages (MP). The study was conducted on macrophage-like cells of the THP-1 cell line of two differentiation terms, 3 and 5 days (3d and 5d). Adiponectin (10 μg/mL) stimulated the expression of apoA-1 gene at the mRNA level in 5d MP, but not in 3d MP. The level of apoE mRNA in MP under the action of adiponectin was not affected. Adiponectin suppressed macrophage TNF gene expression, while it induced the expression of IL-10 gene in 5d MP. The secreted levels of apoA-1 and apoE proteins under the action of adiponectin in macrophages of both periods of differentiation remained unchanged, while the level of the surface apoA-1 protein in 5d MP was decreasing. Incubation of 5d MP with the PPARα nuclear receptor antagonist MK-886 or with the nuclear receptor LXR agonist TO-901317 resulted in cancellation of the stimulating effect of adiponectin on apoA-1 gene expression. These data indicate that adiponectin, in addition to its anti-inflammatory action, has a modulating effect on production of apoA-1 by macrophages. The latter is probably one of the mechanisms of the influence of this adipokine on atherogenesis.

Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis.

Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to determine to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-associated proinflammatory cytokines mimicked this reduction in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced reduction in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS.

Secreted Factors from Adipose Tissue Reprogram Tumor Lipid Metabolism and Induce Motility by Modulating PPARα/ANGPTL4 and FAK

Recent studies indicate that adipose tissue in obesity promotes breast cancer progression by secreting protumorigenic chemokines, growth factors, and fatty acids. However, the detailed mechanisms by which hypertrophic adipose tissue influences breast cancer cells are still not well understood. Here we show that co-culture with adipose tissue from high-fat diet induced obese C57BL/6 mice alters transcriptome profiles in triple-negative breast cancer (TNBC) cells, leading to upregulation of genes involved in inflammation and lipid metabolism, such as IL1B, PLIN2, and ANGPTL4. Similar results were obtained by treating TNBC cells with adipose tissue conditioned media (ACM) generated from fat tissue of obese female patients. Many of the upregulated genes were activated by PPAR nuclear receptors, as shown by pathway analyses and gene expression experiments using PPAR agonists and antagonists. Metabolic analysis revealed that TNBC cells cultivated with ACM had significantly higher levels of β-oxidation. Furthermore, ACM-treated TNBC cells displayed a pronounced aggressive cell phenotype, with enhanced wound healing, proliferation, and invasion capabilities. ACM-induced invasion was dependent on the PPAR-target ANGPTL4 and activated FAK signaling, as shown by ANGPTL4 depletion and FAK inhibition. Together, our data suggest that factors released by adipose tissue change PPAR-regulated gene expression and lipid metabolism and induce a more aggressive TNBC cell phenotype. These effects are, at least in parts, mediated by fatty acids provided by the adipose tissue. IMPLICATIONS: Adipose tissue provides factors for increased progression of TNBC cells, identifying PPAR- and FAK-signaling as potential novel targets for treatment of TNBC, especially in obese women.

Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease.

Triclosan (TCS), employed as an antiseptic and disinfectant, comes into direct contact with humans through a plethora of consumer products and its rising environmental release. We have demonstrated that TCS promotes liver tumorigenesis in mice, yet the biological and molecular mechanisms by which TCS exerts its toxicity, especially in early stages of liver disease, are largely unexplored. When mice were fed a high-fat diet (HFD), we found that fatty liver and dyslipidemia are prominent early signs of liver abnormality induced by TCS. The presumably protective HFD-induced hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21) was blunted by TCS. TCS-altered Fgf21 expression aligned with aberrant expression of genes encoding metabolic enzymes manifested as profound systemic metabolic changes that disturb homeostasis of amino acids, fatty acids, and glucose. Using a type 1 diabetic animal model, TCS potentiates and accelerates the development of steatohepatitis and fibrosis, accompanied by increased levels of hepatic lipid droplets and oxidative stress. Analysis of fecal samples revealed that HFD-fed mice exhibited a reduction in fecal species richness, and that TCS further diminished microbial diversity and shifted the bacterial community toward lower Bacteriodetes and higher Firmicutes, resembling changes in microbiota composition in nonalcoholic steatohepatitis (NASH) patients. Using reverse-genetic approaches, we demonstrate that, along with HFD, TCS induces hepatic steatosis and steatohepatitis jointly regulated by the transcription factor ATF4 and the nuclear receptor PPARα, which participate in the transcriptional regulation of the Fgf21 gene. This study provides evidence linking nutritional imbalance and exposure to TCS with the progression of NASH.

Retinal homeostasis and metformin-induced protection are not affected by retina-specific Pparδ knockout

Peroxisome proliferator-activated receptors (PPARs) are a family of three nuclear hormone receptors (PPARα, PPARδ, and PPARγ) that are known to regulate expression of lipid metabolism and oxidative stress genes. Given their role in reducing oxidative stress in a variety of tissues, these genes are likely important for retinal homeostasis. This hypothesis has been further supported by recent studies suggesting that PPAR-activating drugs are protective against retinal degenerations. The objective of the present study was to determine the role of PPARδ in the neuroretina. RNA-seq data show that Pparα and Pparδ are both expressed in the retina, but that Pparδ is expressed at 4-fold higher levels. Single-cell RNAseq data show that Pparδ is broadly expressed in all retinal cell types. To determine the importance of Pparδ to the retina, we generated retina-specific Pparδ knockout mice. We found that deletion of Pparδ had a minimal effect on retinal function or morphology out to 12 months of age and did not increase retinal sensitivity to oxidative stress induced by exposure to bright light. While data show that PPARδ levels were increased by the drug metformin, PPARδ was not necessary for metformin-induced protection from light damage. These data suggest that Pparδ either has a redundant function with Pparα or is not essential for normal neuroretina function or resistance to oxidative stress.