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Distinct but complementary contributions of PPAR isotypes to energy homeostasis
Vanessa Dubois, … , Philippe Lefebvre, Bart Staels
Vanessa Dubois, … , Philippe Lefebvre, Bart Staels
Published April 3, 2017
Citation Information: J Clin Invest. 2017;127(4):1202-1214. https://doi.org/10.1172/JCI88894.
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Review Series

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

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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.

Authors

Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels

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Figure 1

PPARα activation stimulates FA and triglyceride metabolism.

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PPARα activation stimulates FA and triglyceride metabolism.
During fasti...
During fasting (yellow), FAs released from WAT are taken up by the liver and transported to mitochondria, where FAO takes place, to produce acetyl-CoA (AcCoA), which can be further converted to ketone bodies and serve as fuel for peripheral tissues. In the fed state (green), acetyl-CoA is shuttled to the cytosol, where DNL takes place. The effects of PPARα activation and PPARα target genes are indicated in pink. FAO is also stimulated by PPARα in WAT and SKM. By regulating hepatic apolipoprotein synthesis, PPARα activation decreases plasma levels of triglycerides (TG) and LDL-C and increases HDL-C. PPARα also acts on BAT, gut, and pancreas, but its central effects are unclear. Blue brackets indicate PPARα actions that are mainly restricted to mice and do not occur (e.g., peroxisome proliferation, reduced liver fat content) or occur to a lesser extent (e.g., reduced APO-B production) in humans. ACAD, acyl-CoA dehydrogenase; ACC, acetyl-CoA carboxylase; CM, chylomicron; CPT, carnitine palmitoyltransferase; FACoA, fatty acyl-CoA; FAS, fatty acid synthase; FATP, fatty acid transport protein.

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