Liver fat storage is controlled by HNF4α through induction of lipophagy and is reversed by a potent HNF4α agonist

We report the discovery of strong HNF4 alpha agonists and their use to uncover a previously unknown pathway by which HNF4 alpha 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 HNF4 alpha. The HNF4 alpha 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 HNF4 alpha activators. In vitro, NCT and NFT induced fat clearance from palmitate-loaded cells. In DIO mice, NCT led to recovery of hepatic HNF4 alpha expression and reduction of steatosis. Mechanistically, increased dihydroceramide production and action downstream of HNF4 alpha occurred through increased expression of HNF4 alpha 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.