Tumor necrosis factor alpha-induced activation of SREBP2 promotes cholesterol biosynthesis in cholestasis

Abstract

Background and aims

Cholestasis is frequently associated with lipid metabolism disorders, elevated cholesterol levels and disruptions in bile acid homeostasis. Nevertheless, the mechanisms underlying cholesterol elevation in cholestasis remain inadequately understood. This study aims to investigate alterations in cholesterol levels and potential mechanisms in mouse models of cholestasis. Additionally, we evaluate the therapeutic potential of Sterol Regulatory Element Binding Protein 2 (SREBP2), a key transcription factor regulating cholesterol synthesis, in treating cholestasis.

Approaches and results

We developed mouse models of cholestasis using bile duct ligation (BDL) and a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Serum and liver samples were collected for analysis. The human hepatoma cell line PLC/RPF/5 was used for mechanistic studies. Cholestatic mice exhibited significantly elevated total cholesterol levels in serum and liver. Gene expression analysis revealed marked upregulation of cholesterol biosynthesis-related genes and the transcription factor SREBP2. Mechanistic studies indicated that TNFα promotes cholesterol synthesis by activating SREBP2 and its downstream target genes. To validate these findings in vivo, we employed the BDL mouse model and treated the mice with Fatostatin, a known SREBP2 inhibitor. Administration of Fatostatin significantly reduced serum ALT, ALP and hepatic cholesterol levels in the BDL mouse model, suggesting a potential therapeutic effect against cholestatic liver injury.

Conclusions

This study concludes that the activation of the NF-κB signaling pathway by TNFα leads to increased expression of SREBP2 in cholestatic mouse model. These findings indicate that the TNFα/NF-κB/SREBP2 pathway could serve as a promising target for treating cholestasis.