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 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.