Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells

Elevated levels of free fatty acids (FFAs) in the liver, resulting fromeither increased lipolysisor imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study wasconducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturallyoccurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosisin human hepatocellular carcinoma cells and to elucidate the underlying mechanism.HepG2 cells were incubated with OA to induce steatosis, and then treated with variousconcentrations of THC. The results showed that THC treatment significantly decreasedlipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of thelipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisomeproliferator-activated receptor gamma (PPARg), fatty acid synthase (FAS), and fatty acidbindingprotein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis inan adenosine monophosphateeactivated protein kinase (AMPK)-dependent manner,which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis andupregulated the expression of genes involved in b-oxidation. Glucose uptake and insulinsignaling impaired in HepG2 cells incubated with OA were abated by THC treatment,including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1)and glycogen synthase kinase 3 b (GSK3b), which are involved in gluconeogenesis andglycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeuticbenefit of THC against hepatic steatosis and, consequently, a potential treatment fornon-alcoholic fatty liver disease (NAFLD).