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Abstract Osthole, a coumarin derivative, can increase hepatic peroxisome proliferator-activated receptor α (PPARα) expression and reduce hepatic steatosis and inflammatory response in rats with non-alcoholic steatohepatitis (NASH). In this study, a cell model of NASH was induced with oleic acid (OA)/lipopolysaccharide (LPS) and treated for 36 h with different osthole concentrations. Results showed that intracellular lipid and inflammatory cytokine levels gradually decreased after osthole treatment. These effects, however, were abolished or attenuated after PPARα gene silencing. Accordingly, PPARα gene silencing reversed the osthole-mediated expressions of proteins involved in lipid synthesis and fatty acid oxidation. PPARα gene silencing also abrogated the inhibitory effect of osthole on nuclear factor kappa B p65 protein expression. These findings demonstrate that osthole activates PPARα signaling pathway to inhibit lipid accumulation and inflammatory response in OA/LPS-stimulated hepatocytes. Highlights • Osthole inhibited lipid accumulation and inflammatory response in hepatocytes. • Osthole regulated protein expressions related to lipid metabolism by activating PPARα. • Osthole inhibited NF-κB p65 protein expression by activation of PPARα. [ABSTRACT FROM AUTHOR]

Our previous studies have indicated that osthole may ameliorate the hepatic lipid metabolism and inflammatory response in nonalcoholic steatohepatitic rats, but the underlying mechanisms remain unclear. This study aimed to determine whether the effects of osthole were mediated by the activation of hepatic peroxisome proliferator-activated receptor α/γ (PPARα/γ). A rat model with steatohepatitis was induced by orally feeding high-fat and high-sucrose emulsion for 6 weeks. These experimental rats were then treated with osthole (20 mg/kg), PPARα antagonist MK886 (1 mg/kg) plus osthole (20 mg/kg), PPARγ antagonist GW9662 (1 mg/kg) plus osthole (20 mg/kg) and MK886 (1 mg/kg) plus GW9662 (1 mg/kg) plus osthole (20 mg/kg) for 4 weeks. The results showed that after osthole treatment, the hepatic triglycerides, free fatty acids, tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-8 and liver index decreased by 52.3, 31.0, 32.4, 28.9, 36.3, 29.3 and 29.9%, respectively, and the score of steatohepatitis also decreased by 70.0%, indicating that osthole improved the hepatic steatosis and inflammation. However, these effects of osthole were reduced or abrogated after simultaneous addition of the specific PPARα antagonist MK886 or/and the PPARγ antagonist GW9662, especially in the co-PPARα/γ antagonists-treated group. Importantly, the osthole-induced hepatic expressions of PPARα/γ proteins were decreased, and the osthole-regulated hepatic expressions of lipogenic and inflammatory gene proteins were also reversed by PPARα/γ antagonist treatment. These findings demonstrated that the ameliorative effect of osthole on nonalcoholic steatohepatitis was mediated by PPARα/γ activation, and osthole might be a natural dual PPARα/γ activator. [ABSTRACT FROM AUTHOR]