Glycyrrhetinic acid attenuates disturbed vitamin a metabolism in non-alcoholic fatty liver disease through AKR1B10

Abstract

Abnormal vitamin A (retinol) metabolism plays an important role in the occurrence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In this study, NAFLD and NASH models were established to investigate the effects of food additives glycyrrhizic acid (GL) on retinol metabolism in NAFLD/NASH mice. Potential targets of GL and its active metabolite glycyrrhetinic acid (GA) were analyzed by RNA sequence, bioinformatics, and molecular docking analyses. Gene transfection and enzymatic kinetics were used to identify the target of GL. The results showed that GL could resolve the fatty and inflammatory lesions in the mouse liver, thereby improving the disorder of retinol metabolism. RNA sequence analysis of model mice liver revealed significant changes in AKR1B10 (retinol metabolic enzymes). Bioinformatics and molecular docking analyses showed that AKR1B10 is a potential target of GA but not GL. GA could inhibit AKR1B10 activity, which then affects retinol metabolism, whereas GL only had the same effect after hydrolysis into GA. In AKR1B10-KO hepatocytes, GA, GL, and hydrolysates of GL had no regulatory effect on retinol metabolism. Therefore, GA, the active metabolite of GL, as a novel AKR1B10 inhibitor, could promote retinoic acid synthesis. GL restored the balance of retinol metabolism in NAFLD/NASH mice by metabolizing to GA.