n-caffeoyltyramine and feruloyltyramine

We report the discovery of strong HNF4α agonists and their use to uncover a previously unknown pathway by which HNF4α controls the level of fat storage in the liver. This involves the induction of lipophagy by dihydroceramides, the synthesis and secretion of which is controlled by genes induced by HNF4α. The HNF4α activators are N-trans caffeoyltyramine (NCT) and N-trans feruloyltyramine (NFT), which are structurally related to the known drugs alverine and benfluorex, which we previously showed to be weak HNF4α activators. In vitro, NCT and NFT induced fat clearance from palmitate-loaded cells. In DIO mice, NCT led to recovery of hepatic HNF4α expression and reduction of steatosis. Mechanistically, increased dihydroceramide production and action downstream of HNF4α occurred through increased expression of HNF4α downstream genes, including SPNS2 and CYP26A1. NCT was completely nontoxic at the highest dose administered and so is a strong candidate for an NAFLD therapeutic.

Topics: Animals; Autophagy; Caffeic Acids; Cells, Cultured; Coumaric Acids; HeLa Cells; Hep G2 Cells; Hepatocyte Nuclear Factor 4; Humans; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Tyramine

Typheramide (N-caffeoyltyramine) and alfrutamide (N-feruloyltyramine) are phenylpropenoic acid amides found in plants. In this article, typheramide and alfrutamide were isolated from Allium sativum (garlic) and Allium fistulosum (green onion), their chemical structures were confirmed using nuclear magnetic resonance spectroscopic methods, and the potential effects on cyclooxygenases (COXs) (COX 1 and 2) and lipoxygenases (LOXs) (5- and 15-LOX) were investigated. Typheramide and alfrutamide inhibited COX 1 by 74% (P < .01) and 60% (P < .01), respectively, at the concentration of 0.1 μM; at the same concentration, they also inhibited COX 2 by 68% (P < .02) and 54% (P < .02), respectively. Typheramide was slightly stronger than alfrutamide in inhibiting COX enzymes, and the inhibition patterns of COX 1 and 2 were uncompetitive with K(i) = 0.032 and 0.047 μM, respectively. However, typheramide and alfrutamide were not able to inhibit 5-LOX, and they only moderately inhibited 15-LOX by 27% (P < .02) and 17% (P < .02), respectively, at the relatively high concentration of 25 μM. Altogether, the data suggest that typheramide and alfrutamide from garlic and green onions are likely to be significant inhibitors for COX 1 and 2 rather than 5- and 12-LOX.

Topics: Allium; Caffeic Acids; Coumaric Acids; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Lipoxygenases; Plant Extracts; Tyramine

Plant-specific bioactive compounds including feruloyltyramine (FT), 4-coumaroyltyramine (CT), and caffeoyltyramine (CaT) were simultaneously produced in Escherichia coli by heterologous expression of two biosynthetic genes encoding 4-coumarate:coenzyme A ligase and tyramine N-hydroxycinnamoyltransferase (THT) cloned from Arabidopsis thaliana and pepper, respectively. Simultaneous supplementation of substrates to the recombinant E. coli resulted in the secretion of multiple tyramine derivatives into the medium at high yield: CT (189 mg l(-1)), FT (135 mg l(-1)), CaT (40 mg l(-1)). In addition, the recombinant E. coli also produced, albeit at low concentration, a range of dopamine derivatives such as feruloyldopamine due to THT's ability to accept dopamine as a substrate.

Topics: Acyltransferases; Arabidopsis; Caffeic Acids; Coenzyme A Ligases; Coumaric Acids; Culture Media; Escherichia coli; Gene Expression; Recombinant Proteins; Tyramine