PPAR Agonists and Metabolic Syndrome: An Established Role?

Botta, Margherita; Audano, Matteo; Sahebkar, Amirhossein; Sirtori, Cesare R.; Mitro, Nico; Ruscica, Massimiliano

doi:10.3390/ijms19041197

Cited by 177 publications

(118 citation statements)

References 142 publications

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“…The interest for the use of PPAR-α agonists (mainly fibrates [38]) in anti-NASH treatment arose already two decades ago, when gemfibrozil was tested in patients suffering from NASH. Gemfibrozil reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels, as well as VLDL triglyceride production.…”

Section: Ppar-α Agonistsmentioning

confidence: 99%

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Boeckmans

Natale

Rombaut

et al. 2019

Cells

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Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.

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Section: Ppar-α Agonistsmentioning

confidence: 99%

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Boeckmans

Natale

Rombaut

et al. 2019

Cells

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“…Synthetic ligands for PPARα are fibrates used in treating hypertriglyceridemia (the effectiveness of the use of fibrates is rather low for other PPAR isoforms); PPARβ/δ synthetic ligands are GW501516, GW0742, and L-165041; PPARγ synthetic ligands are thiazolidinediones widely used for the treatment of diabetes and having pronounced antiinflammatory properties [33,37,38,46,89,145]. There is evidence of the effectiveness of using thiazolidinediones as ligands for other PPAR isoforms [90,146].…”

Section: Syntheticmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

et al. 2020

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The complexity of the pathogenetic mechanisms of the development of chronic inflammation in asthma determines its heterogeneity and insufficient treatment effectiveness. Nuclear transcription factors, which include peroxisome proliferatoractivated receptors, that is, PPARs, play an important role in the regulation of initiation and resolution of the inflammatory process. The ability of PPARs to modulate not only lipid homeostasis but also the activity of the inflammatory response makes them an important pathogenetic target in asthma therapy. At present, special attention is focused on natural (polyunsaturated fatty acids (PUFAs), endocannabinoids, and eicosanoids) and synthetic (fibrates, thiazolidinediones) PPAR ligands and the study of signaling mechanisms involved in the implementation of their anti-inflammatory effects in asthma. This review summarizes current views on the structure and function of PPARs, as well as their participation in the pathogenesis of chronic inflammation in asthma. The potential use of PPAR ligands as therapeutic agents for treating asthma is under discussion.

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“…considerably effective in treating and managing metabolic syndrome, some of the approved drugs have been retracted from the market or their usage has been curtailed because of harmful side effects (94). Recently, some reviews have already discussed the exhaustive list of agonists and their clinical trial status for each PPAR isotype (95)(96)(97)(98). Therefore, in this review, we will only briefly highlight a few of the promising new drugs that are still undergoing intensive evaluation in human clinical trials.…”

Section: Pparsmentioning

confidence: 99%

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

Visvalingam

Wahli

2019

FASEB j.

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The human gut is colonized by commensal microorganisms, predominately bacteria that have coevolved in symbiosis with their host. The gut microbiota has been extensively studied in recent years, and many important findings on how it can regulate host metabolism have been unraveled. In healthy individuals, feeding timing and type of food can influence not only the composition but also the circadian oscillation of the gut microbiota. Host feeding habits thus influence the type of microbe‐derived metabolites produced and their concentrations throughout the day. These microbe‐derived metabolites influence many aspects of host physiology, including energy metabolism and circadian rhythm. Peroxisome proliferator‐activated receptors (PPARs) are a group of ligand‐activated transcription factors that regulate various metabolic processes such as fatty acid metabolism. Similar to the gut microbiota, PPAR expression in various organs oscillates diurnally, and studies have shown that the gut microbiota can influence PPAR activities in various metabolic organs. For example, short‐chain fatty acids, the most abundant type of metabolites produced by anaerobic fermentation of dietary fibers by the gut microbiota, are PPAR agonists. In this review, we highlight how the gut microbiota can regulate PPARs in key metabolic organs, namely, in the intestines, liver, and muscle. Knowing that the gut microbiota impacts metabolism and is altered in individuals with metabolic diseases might allow treatment of these patients using noninvasive procedures such as gut microbiota manipulation.—Oh, H. Y. P., Visvalingam, V., Wahli, W. The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology. FASEB J. 33, 9706–9730 (2019). http://www.fasebj.org

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PPAR Agonists and Metabolic Syndrome: An Established Role?

Cited by 177 publications

References 142 publications

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

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