The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment

Abstract

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor ␣ (PPAR␣) and PPAR␤/␦ agonists in rat and human hepatoma cell lines and by PPAR␥ and PPAR␤/␦ agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPAR␣ agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form.

Enterococcus faecalis from newborn babies regulate endogenous PPARγ activity and IL-10 levels in colonic epithelial cells

“…Time points of gene expression evaluation were set to 6 h to account for early transcriptional events. The effects on target gene expression were assessed, where the target gene, ADRP (or adipophilin), along with yet another PPAR␥ target gene, FIAF (or angiopoietin-like protein 4) (19,20), were strongly induced by EC16 as well as a PPAR␥-specific ligand, rosiglitazone (Fig. 3 A and B).…”

Angiopoietin-like 4 Interacts with Matrix Proteins to Modulate Wound Healing*

“…The specificity of anti-cANGTPL4 is shown in supplemental Fig. S1A and specificity of anti-nANGPTL4 was as previously reported (15). Day 3 wound biopsies were used because PPAR␤/␦ expression peaked at day 3 postwounding (31).…”

“…Its expression is up-regulated by PPAR (15) and by hypoxia (16). ANGPTL4 is also implicated in breast cancer metastasis via the regulation of vascular integrity (17,18).…”

Proteolytic Processing of Angiopoietin-like Protein 4 by Proprotein Convertases Modulates Its Inhibitory Effects on Lipoprotein Lipase Activity

“…In a human study, treatment with fenofibrate, a potent peroxisome proliferator-activated receptor-␣ agonist, markedly increased plasma levels of cleaved ANGPTL4. On this basis, it was proposed that the cleaved form of ANGPTL4 may have specific functions (14). There is evidence that the antiangiogenic activity of ANGPTL4 is regulated by an interaction of its coiled-coil domain with heparan sulfate proteoglygans (HSPGs) (18).…”

“…Interestingly, these two domains are separated by a short linker that can be cleaved after secretion. The cleavage phenomenon has been shown to occur in humans as well as in rodents (13,14). Cleavage of ANGPTL4 appears to be tissue-dependent in humans; liver secretes cleaved ANGPTL4, whereas adipose tissue secretes the fulllength form (14).…”