Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg . SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1a expression. Bioinformatic analysis further predicted the implication of master transcription factors, including peroxisome proliferator-activated receptor alpha (PPAR α ), in the protective effects of SSa and SSd. These results were further confirmed in vitro in mouse primary hepatocytes. In summary, our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins (SSs), and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.

Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

“…For in vivo experiments, the doses of AO (5,10 and 15 mg/kg) were selected based on recent publications ( Xu et al, 2019 ; Guo et al, 2021 ). In chronic HFSW experiment (n = 6), mice were divided into five groups: 1) control group (chow diet); 2) NAFLD model group [HFSW, Western diet-42% Kcal from fat and 0.2% cholesterol (TD.88137, Harlan Laboratories, Inc., Indianapolis, IN, United States) plus with a high sugar solution ( d -fructose: 23.1 g/L and d -glucose: 18.9 g/L) in drinking water ( Li et al, 2021 )]; (3–5) HFSW diet with AO administration group. Mice in groups (2–5) were first fed with the HFSW diet for 4 weeks to induce liver steatosis followed by orally given different doses of AO (5, 10 and 15 mg/kg) or vehicle control for another 4 weeks.…”

“…Oil-red staining was performed as previous established conditions ( Li et al, 2021 ). Oil-red powder was first dissolved in isopropanol solution (0.5 g/ml).…”

“…Western blot analysis was carried out as previously described ( Li et al, 2021 ). Briefly, liver tissues and cell samples were lysed in RIPA lysis buffer.…”

Protective Effects of Tiaoganquzhi Decoction in Treating inflammatory Injury of Nonalcoholic Fatty liver Disease by Promoting CGI-58 and Inhibiting Expression of NLRP3 Inflammasome

“…Salvigenin improve the metabolic syndrome symptoms by decreasing lipid levels and stimulating mitochondrial functionality and it also help cells to survive by inhibiting apoptosis and enhancing autophagy ( Rafatian et al, 2012 ; Serino et al, 2021 ). Saikosaponin A, modulate glycerolipid metabolism role by regulating Lipe and Lipg and transcription factors peroxisome proliferator-activated receptor alpha (PPARa) ( Li et al, 2021 ).…”

Saikosaponins: A Review of Structures and Pharmacological Activities

“…83 SSD (5 µM) prevents the activation of hepatic stellate cells induced by OS depend on ERβ activity, and may be at partially attributed to inhibition of the ROS/MAPK signaling pathway. 84 Li et al 85 found that both SSA(5,10, and 20 mg/kg) and SSD (5, 10, and 20 mg/kg) improved diet-induced Nonalcoholic Fatty Liver Disease (NAFLD). Integrative lipidomic and transcriptomic analysis revealed that SSA and SSD modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg.…”