Hepatic retinoic acid receptor alpha mediates all‐trans retinoic acid's effect on diet‐induced hepatosteatosis

All‐trans retinoic acid (AtRA) is an active metabolite of vitamin A that influences many biological processes in development, differentiation, and metabolism. AtRA functions through activation of retinoid acid receptors (RARs). AtRA is shown to ameliorate hepatic steatosis, but the underlying mechanism is not well understood. In this study, we investigated the role of hepatocyte RAR alpha (RARα) in mediating the effect of AtRA on hepatosteatosis in mice. Hepatocyte‐specific Rarα−/− (L‐Rarα−/−) mice and their control mice were fed a chow diet, high‐fat diet (HFD), or a high‐fat/cholesterol/fructose (HFCF) diet. Some of the mice were also treated with AtRA. Loss of hepatocyte RARα‐induced hepatosteatosis in chow‐fed aged mice and HFD‐fed mice. AtRA prevented and reversed HFCF diet–induced obesity and hepatosteatosis in the control mice but not in L‐Rarα−/− mice. Furthermore, AtRA reduced hepatocyte fatty acid uptake and lipid droplet formation, dependent on hepatocyte RARα. Our data suggest that hepatocyte RARα plays an important role in preventing hepatosteatosis and mediates AtRA's effects on diet‐induced hepatosteatosis. Loss of hepatocyte retinoic acid receptor alpha (RARa) induces liver steatosis in aged mice or high fat diet‐fed mice. All‐trans retinoic acid attenuates diet‐induced hepatosteaosis largely dependent on activation of hepatocyte RARa.