Distinct but complementary contributions of PPAR isotypes to energy homeostasis

Abstract

Peroxisome proliferator-activated receptors (PPARs) regulate energy metabolism and hence are therapeutic targets in metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. In this Review we discuss the complementary and distinct metabolic effects of the PPAR isotypes together with the underlying cellular and molecular mechanisms, as well as the synthetic PPAR ligands that are used in the clinic or under development. We highlight the potential of new PPAR ligands with improved efficacy and safety profiles in the treatment of complex metabolic disorders.

MEX3A regulates Lgr5 + stem cell maintenance in the developing intestinal epithelium

“…The PPAR family of nuclear receptors is comprised of three different isotypes (alpha, beta/delta and gamma) with distinct tissue distribution and ligand specificities. Their activation by endogenous ligands leads to the transactivation of target genes mainly involved in metabolic homeostasis, namely lipid and glucose metabolism [49]. We started by exploring a putative role of MEX3A in the regulation of the PPAR transcription factors by performing transfection experiments in the liver cell line HepG2, which expresses the three PPAR members.…”

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…Although there are no pharmacological options for the treatment of NASH or fibrosis, a few potentially valuable molecules are currently under clinical evaluation. For example, activation of the PPAR nuclear receptors in preclinical models protects from dietary-induced or genetically induced NASH and fibrosis (18,19). Assessment of the translation of such observations to human pathology is currently underway.…”

In vivocharacterisation of the toxicological properties of DPhP, one of the main degradation products of aryl phosphate esters

“…PPAR is a key coordinator of fast-fed transition at the hepatic level with paradoxical effects 34 .…”

“…First, despite reduction in fatty acid oxidation, this effect may not be sufficient to compensate the lack of fatty acid uptake and production at some threshold of PPAR inhibition or after long-term exposure. Second, other members of the PPAR nuclear receptor family may be perturbed, since they are more directly involved in fat digestion, sterol synthesis and storage of fatty acids in the liver and the white adipose tissue 34 . PPAR and  are thus able to bind the same ligands with a same order of affinity potentially explaining that high doses of DPhP may simultaneously inhibit both types of receptors 39 .…”