The boat load of info...http://www.ncbi.nlm.nih.gov/pubmed/23329136
Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells.
Glineur C, Gross B, Neve B, Rommens C, Chew GT, Martin-Nizard F, Rodríguez-Pascual F, Lamas S, Watts GF, Staels B.
Department of Pulmonary Immunity, Center for Infection and Immunity of Lille, Inserm U1019, CNRS UMR8204, Université Lille Nord de France, Lille, France. firstname.lastname@example.org
Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients.
METHODS AND RESULTS:
FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1.
FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.
Cutting Edge: An In Vivo Requirement for STAT3 Signaling in TH17 Development and TH17-Dependent Autoimmunity1http://www.hindawi.com/journals/ppar/2012/145654/
Timothy J. Harris*, Joseph F. Grosso*, Hung-Rong Yen*, Hong Xin†, Marcin Kortylewski†, Emilia Albesiano*, Edward L. Hipkiss*, Derese Getnet*, Monica V. Goldberg*, Charles H. Maris*, Franck Housseau*, Hua Yu†, Drew M. Pardoll* and Charles G. Drake2,*
+ Author Affiliations
*Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231; and
†Division of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91019
STAT3 activation has been observed in several autoimmune diseases, suggesting that STAT3-mediated pathways promote pathologic immune responses. We provide in vivo evidence that the fundamental role of STAT3 signaling in autoimmunity relates to its absolute requirement for generating TH17 T cell responses. We show that STAT3 is a master regulator of this pathogenic T cell subtype, acting at multiple levels in vivo, including TH17 T cell differentiation and cytokine production, as well as induction of RORγt and the IL-23R. Neither naturally occurring TH17 cells nor TH17-dependent autoimmunity occurs when STAT3 is ablated in CD4 cells. Furthermore, ablation of STAT3 signaling in CD4 cells results in increased TH1 responses, indicating that STAT3 signaling skews TH responses away from the TH1 pathway and toward the TH17 pathway. Thus, STAT3 is a candidate target for TH17-dependent autoimmune disease immunotherapy that could selectively inhibit pathogenic immune pathways.
Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases.http://www.rndsystems.com/cb_detail_obj ... ation.aspx
Th17 Differentiation: An Evolving Target for Multiple Sclerosis Therapyhttp://onlinelibrary.wiley.com/doi/10.1 ... 875.x/full
Peroxisome proliferator-activated receptor-α agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosishttp://www.jimmunol.org/content/172/9/5790.short
The interleukin-12 (IL-12) family of cytokines which includes IL-12, IL-23, and IL-27 play critical roles in T cell differentiation and are important modulators of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Previously, we demonstrated that peroxisome proliferator-activated receptor (PPAR) -α agonists suppress the development of EAE. The present studies demonstrated that the PPAR-α agonist fenofibrate inhibited the secretion of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 by lipopolysaccharide-stimulated microglia. The cytokines interferon-γ and tumor necrosis factor-α also stimulated IL-12 p40 and IL-27 p28 expression by microglia, which was suppressed by fenofibrate. Furthermore, fenofibrate inhibited microglial expression of CD14 which plays a critical role in TLR signaling, suggesting a mechanism by which this PPAR-α agonist regulates the production of these pro-inflammatory molecules. In addition, fenofibrate suppressed the secretion of IL-12p40, IL-23, and IL-27p28 by lipopolysaccharide-stimulated astrocytes. Importantly, fenofibrate suppression of EAE was associated with decreased expression of IL-12 family cytokine mRNAs as well as mRNAs encoding TLR4, CD14, and MyD88 known to play critical roles in MyD88-dependent TLR signaling. These novel observations suggest that PPAR-α agonists including fenofibrate may modulate the development of EAE, at least in part, by suppressing the production of IL-12 family cytokines and MyD88-dependent signaling.
Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease1http://dvdres.com/content/4/3_suppl/S12.short
Amy E. Lovett-Racke*, Rehana Z. Hussain*, Sara Northrop*, Judy Choy*, Anne Rocchini*, Lela Matthes*, Janet A. Chavis‡, Asim Diab*, Paul D. Drew‡ and Michael K. Racke2,*,†
+ Author Affiliations
*Department of Neurology, and
† Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
‡ Department of Neurobiology and Developmental Sciences, University of Arkansas for the Medical Sciences, Little Rock, AR 72205
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ ligands, which include the naturally occurring PG metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), as well as thiazolidinediones, have been shown to have anti-inflammatory activity. The PPARα agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia. In the present study, we demonstrate that these PPARα agonists can increase the production of the Th2 cytokine, IL-4, and suppress proliferation by TCR transgenic T cells specific for the myelin basic protein Ac1–11, as well as reduce NO production by microglia. Oral administration of gemfibrozil and fenofibrate inhibited clinical signs of experimental autoimmune encephalomyelitis. More importantly, gemfibrozil was shown to shift the cytokine secretion of human T cell lines by inhibiting IFN-γ and promoting IL-4 secretion. These results suggest that PPARα agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis.
Extensive data implicate peroxisome proliferator-activated receptor-alpha (PPARα) as an important transcriptional regulator of lipid metabolism, energy balance and inflammation. PPARα is also an established drug target. Experimental data show that activation of PPARα by agonists such as fenofibrate improves dyslipidaemia, increases cholesterol efflux and limits inflammation.http://www.ncbi.nlm.nih.gov/pubmed/22792085
Fenofibrate inhibited the differentiation of T helper 17 cells in vitro.http://www.ncbi.nlm.nih.gov/pubmed/18261709
Zhou Z, Sun W, Liang Y, Gao Y, Kong W, Guan Y, Feng J, Wang X.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
Uncontrolled activity of T cells mediates autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and atherosclerosis. Recent findings suggest that enhanced activity of interleukin-17 (IL-17) producing T helper 17 cells (Th17 cells) plays an important role in autoimmune diseases and inflammatory diseases. Previous papers have revealed that a lipid-lowering synthetic ligand of peroxisome proliferator-activated receptor α (PPARα), fenofibrate, alleviates both atherosclerosis and a few nonlipid-associated autoimmune diseases such as autoimmune colitis and multiple sclerosis. However, the link between fenofibrate and Th17 cells is lacking. In the present study, we hypothesized that fenofibrate inhibited the differentiation of Th17 cells. Our results showed that fenofibrate inhibited transforming growth factor-β (TGF-β) and IL-6-induced differentiation of Th17 cells in vitro. However, other PPARα ligands such as WY14643, GW7647 and bezafibrate did not show any effect on Th17 differentiation, indicating that this effect of fenofibrate might be PPARα independent. Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases.
In patients with non-alcoholic fatty liver disease, treatment with fenofibrate is safe and improves metabolic syndrome, glucose and liver tests. However, its effects on liver histology are minimal.
FGF21 is downregulated in MShttp://www.nextbio.com/b/search/da/FGF2 ... ry=1264130
Fenofibrate increases fgf21 in "healthy" humanshttp://www.researchgate.net/publication ... ion_in_man
The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man.
Cecilia Gälman, Tomas Lundåsen, Alexei Kharitonenkov, Holly A Bina, Mats Eriksson, Ingiäld Hafström, Maria Dahlin, Per Amark, Bo Angelin, Mats Rudling
Department of Endocrinology, Metabolism and Diabetes, Molecular Nutrition Unit, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
Cell metabolism (impact factor: 17.35). 09/2008; 8(2):169-74. DOI:10.1016/j.cmet.2008.06.014
ABSTRACT FGF21 is a critical metabolic regulator, pivotal for fasting adaptation and directly regulated by PPARalpha in rodents. However, the physiological role of FGF21 in man is not yet defined and was investigated in our study. Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, gender, body mass index (BMI), serum lipids, or plasma glucose. FGF21 levels had no diurnal variation and were unrelated to bile acid or cholesterol synthesis. Ketosis induced by a 2 day fast or feeding a ketogenic diet (KD) did not influence FGF21 levels, whereas a 74% increase occurred after 7 days of fasting. Hypertriglyceridemic nondiabetic patients had 2-fold elevated FGF21 levels, which were further increased by 28% during fenofibrate treatment. FGF21 circulates in human plasma and increases by extreme fasting and PPARalpha activation. The wide interindividual variation and the induction of ketogenesis independent of FGF21 levels indicate that the physiological role of FGF21 in humans may differ from that in mice.
Things that worry me:
Fenofibrate reduces tnf-a. Tnf-a antibody has been implicated as a cause for MS onset and increased MRI activity during long term treatment. (I don't plan long term use of fenofibrate without noticeable and significant improvement.)
Fenofibrate causes increased homocysteine. This can be counteracted with b-complex.http://www.ncbi.nlm.nih.gov/pubmed/11500187
Long-term fenofibrate therapy causes endothelial dysfunction. (Another reason to stop if it doesn't cause marked improvement.)http://cardiovascres.oxfordjournals.org ... /398.short
Although it increases NO production through increases in eNOS expression, fenofibrate treatment induces endothelial dysfunction. This effect seems to be mediated by decreased PGI2 and increased PGE2 release, and it may help to explain the rise in thromboembolic events observed after long-term fenofibrate treatment in humans.
PPAR-a can activate RAAS (bumping aldosterone up...counterproductive if it happens)http://hyper.ahajournals.org/content/51/6/1442.full
Potential for liver damage (But could also help liver)http://livertox.nih.gov/Fenofibrate.htmhttp://www.yourpersonalhealthandwellnes ... ing-drugs/
Fibrates (like Tricor or fenofibrate) deplete vitamin B12, vitamin E, copper and zinc. http://dailymed.nlm.nih.gov/dailymed/dr ... m?id=71703
(guess I need to take some inosine with my b's/multi)
Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid
Looks almost as fun as a DMD
Forgot part of my rationale for taking the risk. *If* the fenofibrate works to stop cytokine related crh stimulation and hpa axis activation and therefore reduces some of the very same conditions caused by MS, some of the risk factors could wind up being a wash or result a net improvement.