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The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma , has been reported to ameliorate no-nalcoholic steatohepatitis (NASH) and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. HepG2, HL7702 cells, and C57BL/6J mice were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro. Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro. Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to voltage-dependent anion channel protein-1 (VDAC1). ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum (ER) to golgi apparatus (GA). Further investigations indicated that the activation of AMPK by ALB was independent on classical upstream CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia. [Display omitted] [ABSTRACT FROM AUTHOR]

• DA is a dual-PPAR-α/γ and PPAR-γ partial agonist. • DA alleviates HFD-induced insulin resistance via PPAR-γ. • DA alleviates HFD-induced hepatic steatosis via PPAR-α. Dual-PPAR-α/γ agonist has the dual potentials to improve insulin resistance (IR) and hepatic steatosis associated with obesity. This study aimed to investigate whether dehydroabietic acid (DA), a naturally occurred compound, can bind to and activate both PPAR-γ and PPAR-α to ameliorate IR and hepatic steatosis in high-fat diet (HFD)-fed mice.. We found that DA formed stable hydrogen bonds with the ligand-binding domains of PPAR-γ and PPAR-α. DA treatment also promoted 3T3-L1 differentiation via PPAR-γ activation, and mitochondrial oxygen consumption in HL7702 cells via PPAR-α activation. In HFD-fed mice, DA treatment alleviated glucose intolerance and IR, and reduced hepatic steatosis, liver injury markers (ALT, AST), and lipid accumulation, and promoted mRNA expression of PPAR-γ and PPAR-α signaling elements involved in IR and lipid metabolism in vivo and in vitro , and inhibited mRNA expression of pro-inflammatory factors. Therefore, DA is a dual-PPAR-α/γ and PPAR-γ partial agonist, which can attenuate IR and hepatic steatosis induced by HFD-consumption in mice. [ABSTRACT FROM AUTHOR]

Exploiting efficient catalysts is of interest for solar-driven water splitting. Herein, a novel NiWO 4 /CdS nanosheets-on-nanorods direct Z-Scheme heterostructure was developed by using a facile in-situ approach. The optimized NiWO 4 /CdS heterostructure shows a H 2 evolution rate of 26.43 mmol g−1 h−1 exceeding that of bare CdS by more than 75 folds. Systematic investigations reveal the nanostructures with numerous active sites, intimate contact interface, and enhanced charge separation rate synergistically account for the outstanding performance of the NiWO 4 /CdS. Moreover, the band structures were detailedly analyzed and the tentative photocatalytic mechanism was proposed, which could contribute to deeply understanding the catalytic process and guide the synthesis of the efficient heterostructure. These findings and strategies may have great significance in promoting the development of highly efficient and low-cost photocatalysts. [Display omitted] • A novel NiWO 4 /CdS Z-scheme heterostructure was first constructed by using a facile approach. • The NiWO 4 /CdS exhibits a H 2 evolution rate of 26.43 mmol g−1 h−1 far acceding that of CdS. • The good performance was attributed to the formation of the well-defined heterostructure. • The band energy level and photocatalytic mechanism were detailedly investigated. [ABSTRACT FROM AUTHOR]