PPARα activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans

Subramanian, Savitha; DeRosa, Michael; Bernal‐Mizrachi, Carlos; Laffely, Nicholas; Cade, W. Todd; Yarasheski, Kevin E.; Cryer, Philip E.; Semenkovich, Clay F.

doi:10.1152/ajpendo.00230.2006

Cited by 30 publications

(28 citation statements)

References 37 publications

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“…These observations are supported by observations made in spontaneously hypertensive rats 16 and healthy, human volunteers. 17 The exact role of PPAR-␣ in the regulation of blood pressure remains unclear, because several other studies conducted in various rat models of hypertension have provided inconsistent results. 18,19 It is currently not known whether renin activation associated with PPAR-␣ activation is a direct transcriptional effect of PPAR-␣ or if it should be regarded as a secondary phenomenon, attributable to concomitant blood pressure reduction or other ancillary effects of PPAR agonists (eg, antiinflammatory and antiproliferative effects on the vasculature or increased sympathetic activity).…”

Section: Peroxisome Proliferator-activated Receptorsmentioning

confidence: 99%

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

et al. 2008

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T he renin-angiotensin-aldosterone system (RAAS) has been identified as the main system involved in blood pressure regulation, renal hemodynamics, and sodiumvolume homeostasis. Furthermore, the RAAS directly affects vascular and cardiac remodeling through proliferative and inflammatory signaling. Pharmacological targeting of the RAAS is a consolidated and evidence-based approach in the treatment of various aspects of cardiovascular disease. An exploding number of recent studies have provided novel insights into nuclear receptor biology in relation to cardiovascular (patho)physiology. In particular, members of the nuclear hormone receptor (NHR) superfamily have been identified as key molecules in various relevant cellular processes. As such, NHRs have been proposed as amenable targets for therapy, and their role in cardiovascular disease is currently explored.This review focuses on the potential effects of NHRs on the RAAS, summarizing the extensive body of evidence from experimental, animal, and clinical studies, suggesting that NHRs and the RAAS are closely intertwined. We discuss how these findings might translate into the clinical setting and discuss the (older) trials that evaluated NHR agonists in humans. We postulate that therapies targeting NHRs will cause ancillary effects (ie, modulating the RAAS) that need to be considered.

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Section: Peroxisome Proliferator-activated Receptorsmentioning

confidence: 99%

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

et al. 2008

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“…In the LDL-receptor KO background, GCs increased hepatic gluconeogenic gene expression in a PPAR␣-dependent manner, suggesting a role for PPAR␣ in promoting GC-induced insulin resistance (14). It was further reported by the same group that FENO could not correct DEX-mediated resistance to insulininduced suppression of hepatic Glc production in man (15). Interestingly and completely in line with our findings, in the same clinical study DEX increased basal hepatic Glc production in healthy individuals, whereas combination treatment with FENO decreased DEX-induced hepatic Glc production to baseline or FENO only levels (15).…”

Section: Discussionmentioning

confidence: 95%

PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB

Bougarne

Paumelle

Caron

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoid receptor ␣ (GR␣) and peroxisome proliferatoractivated receptor ␣ (PPAR␣) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor B (NF-B)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPAR␣-and GR␣-mediated signaling pathways. Simultaneous activation of PPAR␣ and GR␣ dose-dependently enhances transrepression of NF-B-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPAR␣ agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPAR␣-dependent manner, as demonstrated by experiments using PPAR␣ wild-type and knockout mice. The underlying mechanism for this transcriptional antagonism relies on a PPAR␣-mediated interference with the recruitment of GR␣, and concomitantly of RNA polymerase II, to GRE-driven gene promoters. Finally, the biological relevance of this phenomenon is underscored by the observation that treatment with the PPAR␣ agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPAR␣ negatively interferes with GREmediated GR␣ activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders.cross-talk ͉ gluconeogenesis ͉ inflammation ͉ hyperinsulinema ͉ side effects G lucocorticoids (GCs) are presently the most potent drugs for the treatment of acute and chronic inflammatory diseases. Nevertheless, side effects such as osteoporosis, muscle wasting, hypertension, behavioral alterations, and disorders of glucose (Glc) and lipid metabolism, burden their therapeutical use. GCs mediate their effect via the glucocorticoid receptor ␣ (GR␣), a member of the nuclear receptor superfamily. After binding of GCs, a conformational change in the receptor is induced, releasing cytosolic chaperoning proteins followed by GR␣ translocation into the nucleus. Activated GR␣ can directly regulate the expression of its target genes through GR␣ binding onto promoter-imbedded GREs. Target genes of GR␣ homodimers include proteins involved in Glc, fat, and protein metabolism. Alternatively, GR␣ can also influence gene expression by interfering with the activity of nuclear factor B (NF-B), a key regulatory proinflammatory transcription factor (1). Peroxisome proliferator-activated receptor ␣ (PPAR␣), a ligand-activated transcription factor, also belonging to the nuclear receptor superfamily, is highly expressed in liver, skeletal and cardiac muscle, kidney, and in cells involved in inflammatory processes. Besides its involvement in lipid and Glc metabolism, PPAR␣ exhibits potent antiinflammatory properties. Recently, a protective role for PPAR␣ has also been demonstrated in obesityinduced hepatic inflammation (2). Fatty acid derivates and hypolipidemic fibrates are natural and synthetic PPAR␣ ligands, respect...

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“…In the FIELD study, there was a placebo-adjusted 2 mmHg systolic and 1 mmHg diastolic reduction in median CBP (6), but in the smaller Diabetes Atherosclerosis Intervention Study (DAIS), there was no significant change (5). By contrast, an uncontrolled short-term study in healthy adults showed that fenofibrate increased ambulatory SBP by 3 mmHg (18). Animal experiments suggest a role for PPAR-␣ in mediating hypertension and atherosclerosis (19), but their relevance to human disease is uncertain.…”

Section: Blood Pressurementioning

confidence: 98%

Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction

et al. 2008

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OBJECTIVE -To investigate the effects of fenofibrate and coenzyme Q 10 (CoQ) on diastolic function, ambulatory blood pressure (ABP), and heart rate (HR) in type 2 diabetic subjects with left ventricular diastolic dysfunction (LVDD).RESEARCH DESIGN AND METHODS -We randomized, double-blind, 74 subjects to fenofibrate 160 mg daily, CoQ 200 mg daily, fenofibrate 160 mg plus CoQ 200 mg daily, or matching placebo for 6 months. Echocardiography (including tissue Doppler imaging) and 24-h ABP and HR monitoring were performed pre-and postintervention.RESULTS -Neither fenofibrate nor CoQ, alone or in combination, altered early diastolic mitral annular myocardial relaxation velocity (EЈ), early-to-late mitral inflow velocity ratio (E/A), deceleration time, isovolumic relaxation time, or the ratio of early mitral flow velocity to early diastolic mitral annular myocardial relaxation velocity (E/EЈ) compared with placebo (P Ͼ 0.05). Fenofibrate and CoQ interactively (P ϭ 0.001) lowered 24-h systolic blood pressure (Ϫ3.4 Ϯ 0.09 mmHg, P ϭ 0.010), with a prominent nocturnal effect (Ϫ5.7 Ϯ 1.5 mmHg, P ϭ 0.006). Fenofibrate (Ϫ1.3 Ϯ 0.5 mmHg, P ϭ 0.013) and CoQ (Ϫ2.2 Ϯ 0.5 mmHg, P Ͻ 0.001) independently lowered 24-h diastolic blood pressure. Fenofibrate reduced 24-h HR (Ϫ3.3 Ϯ 0.5 beats/min, P Ͻ 0.001), but CoQ had no effect on HR.CONCLUSIONS -In type 2 diabetic subjects with LVDD, neither fenofibrate nor CoQ, alone or in combination, improved diastolic function significantly. However, fenofibrate and CoQ independently and interactively lowered 24-h blood pressure, and fenofibrate alone reduced 24-h HR.

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PPARα activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans

Abstract: . PPAR␣ activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans.

Cited by 30 publications

References 37 publications

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB

Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction

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