Berberine-silybin salt achieves improved anti-nonalcoholic fatty liver disease effect through regulating lipid metabolism.

Berberine (BBR) and silybin (SIY) are natural compounds obtained from Berberidaceae members and Silybum marianum (L.) Gaertn. , respectively. These compounds have been demonstrated to regulate lipid metabolism and indue hepatoprotective effects, establishing their importance for the treatment of liver injury. Combination therapy has shown promise in treating ailments with complex pathophysiology, such as liver diseases. However, the inconsistent dissolution and poor absorption of BBR and SIY limit their efficacy. This study compared the salt formulation (BSS) and physical mixture (BSP) of BBR and SIY for their efficacy in treating nonalcoholic fatty liver disease (NAFLD). The formation of the BSS was confirmed using various techniques, including nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and powder X-ray diffractometry. In addition, dissolution, trans-epithelial permeability, and bioavailability experiments were conducted to evaluate the absorption and distribution of drugs. Pharmacodynamics and mechanisms were investigated through in vivo experiments. BSS form demonstrated synchronized dissolution of both components, unlike BSP. Additionally, the transepithelial permeability results revealed that BSS exhibited superior penetration and absorption of both BBR and SIY in comparison to BSP. Furthermore, BSS significantly increased the bioavailability of SIY in both plasma and the liver (2.2- and 4.5-fold, respectively) when compared with BSP. Moreover, BSS demonstrated a more potent inhibitory effect on lipid production in HepG2 cells than BSP. In mouse models (BALB/c) of NAFLD, BSS improved disease outcomes, as evidenced by decreased adipose levels, normalized blood lipid levels, and reduced liver parenchyma injury. Preliminary transcriptomics analysis suggested that BSS achieved its anti-NAFLD effect by regulating the expression of fatty acid transporter CD36, recombinant fatty acid binding protein 4, and stearyl coenzyme A dehydrogenase 1, which are associated with the synthesis and uptake of fatty acid-related proteins. The study demonstrated that compared with physical mixing, salification improved the efficacy of BBR and SIY, as demonstrated in animal experiments. These findings provide valuable insights into the development of more effective treatments for NAFLD and provide new possibilities for combination therapies. Legend: The salt formulation (BSS) of berberine (BBR) and silybin (SIY) exhibited superior efficacy for the treatment of nonalcoholic fatty liver disease (NAFLD). BSS demonstrated a more potent inhibitory effect on lipid formation compared with BBR–SIY physical mixture (BSP). In a mouse model (BALB/c), BSS showed improved disease outcomes, as evidenced by decreased adipose levels, normalized blood lipid levels, and reduced liver parenchyma injury, compared with BSP. BSS mediates its anti-NAFLD effect by regulating the expression of the fatty acid transporter CD36, recombinant fatty acid binding protein 4, and stearyl coenzyme A dehydrogenase 1, which are associated with the synthesis and uptake of fatty acid-related proteins. [Display omitted] • The salt of berberine and silybin exhibits superior effects in treating NAFLD. • The salt shows enhanced penetration and absorption of both berberine and silybin. • Salification resulted in greater efficacy of the two drugs than physical mixing. • This approach addresses the challenge of poor bioavailability of natural compounds. [ABSTRACT FROM AUTHOR]