Practical prospects for boosting hepatic production of the “pro-longevity” hormone FGF21

Fibroblast growth factor-21 (FGF21), produced mainly in hepatocytes and adipocytes, promotes leanness, insulin sensitivity, and vascular health while down-regulating hepatic IGF-I production. Transgenic mice overexpressing FGF21 enjoy a marked increase in median and maximal longevity comparable to that evoked by calorie restriction – but without a reduction in food intake. Transcriptional factors which promote hepatic FGF21 expression include PPARα, ATF4, STAT5, and FXR; hence, fibrate drugs, elevated lipolysis, moderate-protein vegan diets, growth hormone, and bile acids may have potential to increase FGF21 synthesis. Sirt1 activity is required for optimal responsiveness of FGF21 to PPARα, and Sirt1 activators can boost FGF21 transcription. Conversely, histone deacetylase 3 (HDAC3) inhibits PPARα’s transcriptional impact on FGF21, and type 1 deacetylase inhibitors such as butyrate therefore increase FGF21 expression. Glucagon-like peptide-1 (GLP-1) increases hepatic expression of both PPARα and Sirt1; acarbose, which increases intestinal GLP-1 secretion, also increases FGF21 and lifespan in mice. Glucagon stimulates hepatic production of FGF21 by increasing the expression of the Nur77 transcription factor; increased glucagon secretion can be evoked by supplemental glycine administered during post-absorptive metabolism. The aryl hydrocarbon receptor (AhR) has also been reported recently to promote FGF21 transcription. Bilirubin is known to be an agonist for this receptor, and this may rationalize a recent report that heme oxygenase-1 induction in the liver boosts FGF21 expression. There is reason to suspect that phycocyanorubin, a bilirubin homolog that is a metabolite of the major phycobilin in spirulina, may share bilirubin’s agonist activity for AhR, and perhaps likewise promote FGF21 induction. In the future, regimens featuring a plant-based diet, nutraceuticals, and safe drugs may make it feasible to achieve physiologically significant increases in FGF21 that promote metabolic health, leanness, and longevity.

A Natural Polymorphism in Peroxisome Proliferator-Activated Receptor-α Hinge Region Attenuates Transcription due to Defective Release of Nuclear Receptor Corepressor from Chromatin

Peroxisome proliferator-activated receptor-α (PPARα) is a central regulator of lipid metabolism. Fibrate drugs act on PPARα to modulate dyslipidemias. A natural variant (V227A) affecting the PPARα hinge region was associated with perturbations in blood lipid levels in Asian populations. In this study, we investigated the functional significance of the V227A substitution. The variant significantly attenuated PPARα-mediated transactivation of the cytochrome P450 4A6 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) genes in the presence of fibrate ligands. Screening of a panel of PPARα coregulators revealed that V227A enhanced recruitment of the nuclear corepressor NCoR. Transactivation activity of V227A could be restored by silencing NCoR or by inhibition of its histone deacetylase activity. Deletion studies indicated that PPARα interacted with NCoR receptor-interacting domain 1 (ID1) but not ID2 or ID3. These interactions were dependent on the intact consensus nonapeptide nuclear receptor interaction motif in NCoR ID1 and were enhanced by the adjacent 24 N-terminal residues. Novel corepressor interaction determinants involving PPARα helices 1 and 2 were identified. In hepatic cells, the V227A substitution stabilized PPARα/NCoR interactions and caused defective release of NCoR in the presence of agonists on the HMGCS2 promoter. These results provide the first indication that defective function of a natural PPARα variant was due, at least partially, to increased corepressor binding. Our data suggest that the PPARα/NCoR interaction is physiologically relevant and can produce a discernable phenotype when the magnitude of the interaction is altered by a naturally occurring variation.

Fibrates - The Other Life-saving Lipid Drugs

The main controversy in the area of lipid management today is related to the usefulness of �non-statin� agents to maximize cardiovascular risk reduction in particular patient types, such as those with diabetes and metabolic syndrome. Fibrate drugs, such as gemfibrozil (Lopid) and fenofibrate (TriCor), are undoubtedly the best tools to address the condition characterized by high triglycerides, low high-density lipoprotein (HDL), and small dense low-density lipoprotein (LDL) (atherogenic dyslipidemia), but the most recent guidelines from both the American Diabetes Association (ADA) and the National Cholesterol Education Panel continue to focus on LDL control as the target of therapy.