Oleanolic Acid Inhibits SCD1 Gene Expression to Ameliorate Fructose-Induced Hepatosteatosis through SREBP1c-Dependent and -Independent Mechanisms

ScopeThe mechanisms of oleanolic acid (OA) regulating hepatic sterol regulatory element-binding protein (SREBP) 1c/stearoyl-CoA desaturase (SCD) 1 pathway to ameliorate fructose-induced hepatosteatosis are investigated. Methods and resultsRats treated with 10% w/v fructose solution are co-administered by OA for 5 weeks, and then sacrifice after fasting for 14 h. OA reverses the fructose-induced increase in hepatic triglyceride (TG) content and downregulates Scd1 mRNA expression. However, two upstream transcription factors, ChREBP and SREBP1c, remain at normal levels with or without fructose and/or OA. In vivo and in vitro studies using SREBP1c(-/-) mice and HepG2 cell models show that OA also inhibits SCD1 gene overexpression and high hepatic TG levels induced by fructose. On the other hand, in SCD1(-/-) mice, when the fructose diet is supplemented with high levels of oleic acid (OLA) to compensate for the deficiency of SCD1, OA inhibits hepatic SREBP1c and lipogenic gene expression and reduces hepatic OLA (C18:1) production to improve fructose and/or OLA induced liver lipid deposition. Furthermore, OA promotes PPAR alpha and AMPK to enhance fatty acid oxidation in fructose + OLA-fed SCD1(-/-) mice. ConclusionOA may inhibit SCD1 gene expression to ameliorate fructose-induced hepatosteatosis through SREBP1c-dependent and -independent mechanisms.

Automated summary

The study investigates the mechanisms by which oleanolic acid (OA) ameliorates fructose-induced hepatosteatosis through regulating the SREBP1c/SCD1 pathway. The results show that OA can inhibit SCD1 gene expression and reduce hepatic triglyceride levels, thereby improving fructose-induced fatty liver. OA also regulates other transcription factors and enhances fatty acid oxidation to further improve the pathological process.