Idebenone and coenzyme Q10 are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases

Disease Models & Mechanisms
Jens TiefenbachHenry M Krause

Abstract

Current peroxisome proliferator-activated receptor (PPAR)-targeted drugs, such as the PPARγ-directed diabetes drug rosiglitazone, are associated with undesirable side effects due to robust agonist activity in non-target tissues. To find new PPAR ligands with fewer toxic effects, we generated transgenic zebrafish that can be screened in high throughput for new tissue-selective PPAR partial agonists. A structural analog of coenzyme Q10 (idebenone) that elicits spatially restricted partial agonist activity for both PPARα and PPARγ was identified. Coenzyme Q10 was also found to bind and activate both PPARs in a similar fashion, suggesting an endogenous role in relaying the states of mitochondria, peroxisomes and cellular redox to the two receptors. Testing idebenone in a mouse model of type 2 diabetes revealed the ability to reverse fatty liver development. These findings indicate new mechanisms of action for both PPARα and PPARγ, and new potential treatment options for nonalcoholic fatty liver disease (NAFLD) and steatosis.This article has an associated First Person interview with the first author of the paper.

References

Jan 1, 1991·Chemico-biological Interactions·P J O'Brien
May 21, 1999·Science·M MakishimaB Shan
Feb 9, 2000·Molecular Cell Biology Research Communications : MCBRC·G F DaviesW J Roesler
Mar 25, 2000·Journal of Molecular Biology·M TurunenG Dallner
Aug 23, 2000·The Journal of Clinical Investigation·J M Olefsky
Nov 23, 2000·Proceedings of the National Academy of Sciences of the United States of America·R T PetersonS L Schreiber
Nov 1, 1992·Archives of Gerontology and Geriatrics·U SeninM Fioravanti
Nov 27, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jeffrey D BrowningHelen H Hobbs
Feb 16, 2005·International Journal of Obesity : Journal of the International Association for the Study of Obesity·P Puigserver
Jun 16, 2005·Nature Reviews. Molecular Cell Biology·Valentina Perissi, Michael G Rosenfeld
Mar 29, 2007·PPAR Research·Francesc VillarroyaMarta Giralt
Jul 3, 2007·Biochimica Et Biophysica Acta·Barry G Shearer, Andrew N Billin
Oct 19, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shannon Reagan-ShawNihal Ahmad
Mar 29, 2008·Cell Stem Cell·Richard Mark WhiteLeonard I Zon
Apr 4, 2008·Journal of Clinical Biochemistry and Nutrition·Guangzhi JinYorihiro Yamamoto
Jun 4, 2008·Annual Review of Biochemistry·Peter Tontonoz, Bruce M Spiegelman
Dec 17, 2008·Annals of the New York Academy of Sciences·Richard C Scarpulla
Mar 5, 2009·Physiological Genomics·Natalia GuillénJesús Osada
Apr 11, 2009·Journal of Neurology·Klaus KutzPierre Vankan
Feb 24, 2010·Expert Opinion on Drug Safety·Priya Shah, Sunder Mudaliar
Dec 3, 2010·The Journal of Clinical Investigation·Rucha PatelCarolyn L Cummins
Feb 12, 2011·Assay and Drug Development Technologies·Chris DelvecchioHenry M Krause
Jun 28, 2011·Science·Jonathan C CohenHelen H Hobbs
Aug 19, 2011·Journal of Physiology and Biochemistry·Toshikatsu Okumura
Mar 6, 2012·Cell·Varman T Samuel, Gerald I Shulman
Apr 5, 2012·Cardiovascular & Hematological Agents in Medicinal Chemistry·Aamer AbbasDebabrata Mukherjee
Jul 4, 2012·Current Drug Metabolism·M Teresa Donato, M José Gómez-Lechón
Sep 22, 2012·PPAR Research·Vito AnneseSiro Bagnoli
Jul 3, 2013·Cold Spring Harbor Perspectives in Biology·John E Dominy, Pere Puigserver
Jan 1, 2014·Experimental Neurology·Juan Carlos CoronaMichael R Duchen
Nov 25, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Cédric Langhi, Ángel Baldán
Dec 9, 2014·Current Opinion in Cell Biology·Weiwei Fan, Ronald Evans
Jun 7, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Oludemilade AkinrotimiSayeepriyadarshini Anakk

❮ Previous
Next ❯

Citations

Aug 7, 2019·Proceedings of the National Academy of Sciences of the United States of America·Robert D MackinDeborah L Stenkamp
Apr 26, 2020·Antioxidants·Alma MartelliArrigo F G Cicero
Dec 1, 2020·Redox Biology·Nuri GuevenEmma Rybalka
Jan 28, 2021·International Journal of Molecular Sciences·Abraham DanielNuri Gueven
Aug 10, 2021·Journal of Biochemical and Molecular Toxicology·Joy X JiangGino Cortopassi
Jul 23, 2020·Developmental Biology·Jason BurgessBret J Pearson

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
transfection
affinity purification
MDA
electron microscopy
gel filtration
protein assay

Software Mentioned

ImageXpress
Openlab
Xcalibur

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Acta Pharmaceutica : a Quarterly Journal of Croatian Pharmaceutical Society and Slovenian Pharmaceutical Society, Dealing with All Branches of Pharmacy and Allied Sciences
Xin SunMeilin Xie
© 2022 Meta ULC. All rights reserved