Peroxisome Proliferator-Activated Receptor β/δ (PPARβ/δ) but Not PPARα Serves as a Plasma Free Fatty Acid Sensor in Liver

Abstract

Peroxisome proliferator-activated receptor ␣ (PPAR␣) is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically by using high-affinity synthetic agonists. Here we initially set out to elucidate the similarities in gene induction between Wy14643 and fasting. Numerous genes were commonly regulated in liver between the two treatments, including many classical PPAR␣ target genes, such as Aldh3a2 and Cpt2. Remarkably, several genes induced by Wy14643 were upregulated by fasting independently of PPAR␣, including Lpin2 and St3gal5, suggesting involvement of another transcription factor. Using chromatin immunoprecipitation, Lpin2 and St3gal5 were shown to be direct targets of PPAR␤/␦ during fasting, whereas Aldh3a2 and Cpt2 were exclusive targets of PPAR␣. Binding of PPAR␤/␦ to the Lpin2 and St3gal5 genes followed the plasma free fatty acid (FFA) concentration, consistent with activation of PPAR␤/␦ by plasma FFAs. Subsequent experiments using transgenic and knockout mice for Angptl4, a potent stimulant of adipose tissue lipolysis, confirmed the stimulatory effect of plasma FFAs on Lpin2 and St3gal5 expression levels via PPAR␤/␦. In contrast, the data did not support activation of PPAR␣ by plasma FFAs. The results identify Lpin2 and St3gal5 as novel PPAR␤/␦ target genes and show that upregulation of gene expression by PPAR␤/␦ is sensitive to plasma FFA levels. In contrast, this is not the case for PPAR␣, revealing a novel mechanism for functional differentiation between PPARs.Hepatic lipid metabolism is governed by a complex interplay between hormones, transcription factors, and energy substrates, allowing for rapid adaptations to changes in metabolic needs (21). According to the traditional view, energy substrates such as fatty acids influence lipid metabolism by promoting flux through a particular pathway via mass action. However, it has become clear that energy substrates can also directly govern the transcription of enzymes involved in lipid metabolism via mechanisms analogous to those of many hormones. Indeed, it is now evident that glucose and fatty acids play a major regulatory role in hepatic lipid metabolism via direct activation or inhibition of specific transcription factors, including carbohydrate response element binding protein (6, 63), sterol response element binding protein 1 (SREBP1) (2, 41, 58, 61, 62), and peroxisome proliferator-activated receptor ␣ (PPAR␣) (38).Although numerous transcription factors have been shown to be activated by fatty acids in vitro, recent data suggest that PPAR␣ is dominant in mediating the effects of dietary fatty acids on gene expression in liver (48). PPAR␣ is a member of the superfamily of nuclear receptors and is closely related to the other PPAR isoforms, ␤/␦ and ␥ (32). Similar to several other nuclear receptors, PPARs function as heterodimers with the retinoid X receptor and bind to specific sequences on the DNA referred to as PPAR response elements (PPREs) (8,11,26). Numerous studies have shown that fatty acids...

Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans

“…Depending on the type of tissue involved, the effect of fatty acids on ANGPTL4 mRNA can be mediated by different PPAR isotypes ( 18 ). Recently it was shown that PPAR ␦ , but not PPAR ␣ , serves as a plasma FFA sensor in the liver ( 19 ). Krey et al ( 20 ) showed that the affi nity of PPAR ␦ for linoleic acid is higher than for oleic acid, and that 8(S)-HETE (an arachidonic acid metabolite), linolenic, and linoleic acids are the most potent natural ligands for PPAR ␦ .…”

Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype

“…Activation with the synthetic PPARd agonist GW501516 decreases plasma TAG and plasma FFA in dyslipidaemic subjects with central obesity (Ooi et al 2011). PPARd appears to sense and respond to elevated FFA by up-regulating genes such as Lipin 2 (Sanderson et al 2009), and in mice models PPARd agonists have previously been shown to protect against weight gain, steatosis, reduced HDL levels and elevated TAG levels, while PPARd null mice were more susceptible to weight gain (Barish et al 2006). This collectively suggests that activation of PPARd protects against obesity and/or dyslipidaemia.…”

“…The expression levels of selected genes involved in lipid uptake, transport, lipolysis, de novo lipogenesis and fatty acid oxidation were analysed (Table 2). Additionally, we analysed the expression of the transcription factors PPARd and LXRa which have been described as fatty acid sensors regulating genes involved in lipid metabolism (Sanderson et al 2009;Strable and Ntambi 2010). Whereas there were no differences in PBMC gene expression levels of UCP2, HSL and PPARd between normal weight and MHO subjects, ARO subjects had significantly lower expression levels of these genes compared with both normal weight subjects (P = 0.041, P = 0.035 and P = 0.05, respectively) and MHO subjects (P = 0.003, P = 0.003 and P = 0.006, respectively) (Fig.…”

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

“…Studies have identified many ligands that activate and modulate PPAR functions (Berger et al, 1999;Forman et al, 1995;Itoh et al, 2008;Kliewer et al, 1997;Sanderson et al, 2009;Varga et al, 2011). These ligands are summarized in Table 1.…”