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

Abstract

Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling 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 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).

Modulation of the Gut Microbiota during High-Dose Glycerol Monolaurate-Mediated Amelioration of Obesity in Mice Fed a High-Fat Diet

“…(P ϭ 0.002 and P Ͻ 0.001, respectively). Upregulated hepatic PPAR␥ is related to an increased expression of fatty acid binding protein 4 (Fabp4) and the very-low-density lipoprotein receptor (Vldlr) (27,29), which was effectively modified by GML treatment, consistent with lower levels of serum FFA and TG ( Fig. 4e and f) (P Ͻ 0.001 and P ϭ 0.015, respectively).…”

Diphlorethohydroxycarmalol Attenuates Palmitate-Induced Hepatic Lipogenesis and Inflammation

“…FFA is a prominent causative factor of NAFLD [ 40 ], and increased FFA levels have been observed in patients with NAFLD [ 41 , 42 ]. FFA induces excessive TG accumulation in hepatocytes, and this alters lipid metabolism in the liver [ 43 ].…”

Hepatic Lipidomics and Molecular Imaging in a Murine Non-Alcoholic Fatty Liver Disease Model: Insights into Molecular Mechanisms

“…Huang-Qi San reduced both plasma FABP4 levels and liver lipid accumulation in HFD-fed rats [ 59 ]. Tetrahydrocurcumin decreased lipid accumulation in oleic acid-treated HepG2 cells, potentially by inhibiting the expression of Fabp4 among other lipogenic proteins [ 60 ]. Korean red ginseng improved NASH-related inflammation by reducing both FABP4 mRNA and protein levels [ 61 ].…”