Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases which lacks ideal treatment options. Kaempferol and kaempferide, two natural flavonol compounds isolated from Hippophae rhamnoides L., were reported to exhibit a strong regulatory effect on lipid metabolism, for which the mechanism is largely unknown. In the present study, we investigated the effects of kaempferol and kaempferide on oleic acid (OA)-treated HepG2 cells, a widely used in vitro model of NAFLD. The results indicated an increased accumulation of lipid droplets and triacylglycerol (TG) by OA, which was attenuated by kaempferol and kaempferide (5, 10 and 20 μM). Western blot analysis demonstrated that kaempferol and kaempferide reduced expression of lipogenesis-related proteins, including sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1). Expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer binding proteins β (C/EBPβ), two adipogenic transcription factors, was also decreased by kaempferol and kaempferide treatment. In addition, western blot analysis also demonstrated that kaempferol and kaempferide reduced expression of heme oxygenase-1 (HO-1) and nuclear transcription factor-erythroid 2-related factor 2 (Nrf2). Molecular docking was performed to identify the direct molecular targets of kaempferol and kaempferide, and their binding to SCD-1, a critical regulator in lipid metabolism, was revealed. Taken together, our findings demonstrate that kaempferol and kaempferide could attenuate OA-induced lipid accumulation and oxidative stress in HepG2 cells, which might benefit the treatment of NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most common health problems worldwide
To model hepatic steatosis in vitro, HepG2 cells were treated with different concentrations of oleic acid (OA) (0, 0.1, 0.25, 0.5, 0.75, 1 and 2 mM)
Our results demonstrated that kaempferol and kaempferide treatment in HepG2 cells ameliorated the OA-induced increase of sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1), with a dose-dependent manner being observed for kaempferide (Figure 5)
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most common health problems worldwide. The main feature of NAFLD is lipid accumulation without significant alcohol consumption [1,2]. NAFLD could be classified histologically into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) [3]. NAFLD is closely associated with type 2 diabetes, obesity, lipid metabolism dysfunction, atherosclerosis, hypertension and other metabolic disorders [3,4]. The pathogenesis of NAFLD remains unclear, and the “two-hit” hypothesis (recently updated as “multiple hits”) has been a leading theory [5]. The “first hit” is the excessive accumulation of triacylglycerol (TG) and free fatty acids [6], while the “second hit” refers to inflammation, oxidative stress and cellular apoptosis following the “first hit” [7]
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