Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR–α Activators

Abstract

Abstract-Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)-␣ and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)-␣ is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR-␣ is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR-␣ agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-␣, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR-␣ agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR-␣ activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR-␣ agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

“…Student's t -test: * P < 0.05, ** P < 0.01, and *** P < 0.0001 as compared with the Ad-CMV group, respectively. genes involved in bile acid synthesis, including Cyp7a1 and Cyp8b1 ( 21,41 ), and plays a role in modulating infl ammatory responses in the artery wall and liver by interference with the nuclear factor B (NF-B) pathway through direct binding to p65 ( 42 ) and other mechanisms ( 43,44 ).…”

Effect of dietary phenylpropanoid glycoside-based natural extracts on blood parameters and productive performance in intensively-reared young hares

“…There was a significant improvement in some parameters of the lipid profile with a decrease in triglycerides, total cholesterol, and low-density lipoprotein cholesterol (LDL cholesterol) and an increase in HDL cholesterol. The increase in HDL cholesterol concentration in plasma using verbascoside could be due to the effect of polyphenols involved in the regulation of lipid and glucose metabolism which, according to some authors (Norata et al, 2003;van Raalte et al, 2004;Zambon et al, 2006;Bursill and Roach, 2007), activate the PPARα receptor with modulation effects of the expression of key proteins involved in the metabolism of high density lipoprotein (HDL) in the liver. Triglycerides are also involved in the same activation of PPARα by polyphenols, with an induction in the peripheral tissues of the enzyme lipoprotein lipase (LPL) leading to increased lipolysis, which would appear to result in a reduction in circulating triglycerides and a very low density lipoprotein (VLDL).…”

Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo

“…It is noteworthy that the fibrates have been shown to blockade inflammatory cytokine signaling mediated by interleukin-1, interleukin-6, and tumor necrosis factor ␣ via transrepression of nuclear factor-B, C/EBP, activator protein-1, and signal transducer and activator of transcription (Staels et al, 1998;Marx et al, 1999;Devchand et al, 2004;Zambon et al, 2006). Down-regulation of APR genes in our studies suggests that the piperidine agonists can also transrepress the action of nuclear factor-B, C/EBP ␤, and STAT3 in vivo.…”