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Anti-NASH Drug Development Hitches a Lift on PPAR Agonism.
Cells. 2019 12 21; 9(1)C

Abstract

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.

Authors+Show Affiliations

Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

31877771

Citation

Boeckmans, Joost, et al. "Anti-NASH Drug Development Hitches a Lift On PPAR Agonism." Cells, vol. 9, no. 1, 2019.
Boeckmans J, Natale A, Rombaut M, et al. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells. 2019;9(1).
Boeckmans, J., Natale, A., Rombaut, M., Buyl, K., Rogiers, V., De Kock, J., Vanhaecke, T., & M Rodrigues, R. (2019). Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells, 9(1). https://doi.org/10.3390/cells9010037
Boeckmans J, et al. Anti-NASH Drug Development Hitches a Lift On PPAR Agonism. Cells. 2019 12 21;9(1) PubMed PMID: 31877771.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. AU - Boeckmans,Joost, AU - Natale,Alessandra, AU - Rombaut,Matthias, AU - Buyl,Karolien, AU - Rogiers,Vera, AU - De Kock,Joery, AU - Vanhaecke,Tamara, AU - M Rodrigues,Robim, Y1 - 2019/12/21/ PY - 2019/11/25/received PY - 2019/12/15/revised PY - 2019/12/17/accepted PY - 2019/12/28/entrez PY - 2019/12/28/pubmed PY - 2020/9/17/medline KW - elafibranor KW - lanifibranor KW - non-alcoholic fatty liver disease (NAFLD) KW - non-alcoholic steatohepatitis (NASH) KW - peroxisome proliferator-activated receptor (PPAR) KW - pioglitazone KW - saroglitazar JF - Cells JO - Cells VL - 9 IS - 1 N2 - 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. SN - 2073-4409 UR - https://www.unboundmedicine.com/medline/citation/31877771/Anti_NASH_Drug_Development_Hitches_a_Lift_on_PPAR_Agonism_ L2 - https://www.mdpi.com/resolver?pii=cells9010037 DB - PRIME DP - Unbound Medicine ER -