Theacrine ameliorates experimental liver fibrosis in rats by lowering cholesterol storage via activation of the Sirtuin 3-farnesoid X receptor signaling pathway

• Published in: Chemico-biological interactions 2022-09, Vol.364, p.110051-110051, Article 110051
• Main Authors: Lv, Xi-Ting, Wang, Ruo-Hong, Liu, Xiao-Ting, Ye, Yu-Jing, Liu, Xin-Yu, Qiao, Jing-Da, Wang, Guo-En
• Format: Article
• Language: English
• Subjects: Carbon tetrachloride; Cholesterol 7α-hydroxylase; Hepatic stellate cell; Stearoyl-CoA desaturase-1; Sterol 12α-hydroxylase
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2022.110051

Formulations against liver fibrosis (LF) mitigate the progression of hepatitis to cirrhosis. However, notable toxicity of the currently available anti-LF drugs limits their long-term use. In the study, we aimed to investigate the anti-LF effects of theacrine, a purine alkaloid without obvious toxicity, on high-fat diet-, alcohol-, and carbon tetrachloride-induced LF in rats. The results indicated that 10 and 20 mg/kg of theacrine ameliorated hepatic fibrosis, steatosis, and inflammation in LF rats. Mechanistically, theacrine reduced hepatic stellate cell (HSC)-related α-smooth muscle actin expression, and decreased cholesterol accumulation, followed by decreased expression of transforming growth factor-β1, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α. In addition, theacrine upregulated the phosphorylation of AMP-activated protein kinase, accompanied by decreased expression of β-catenin and stearoyl-CoA desaturase 1, and increased the expression of sirtuin 3 (SIRT3). Further investigation revealed that the theacrine-mediated decrease in cholesterol was independent of cholesterol synthesis or low-density lipoprotein (LDL) uptake in hyperlipidemia mice. However, theacrine activated farnesoid X receptor (FXR), a β-catenin conjugated protein, accompanied with decreased expression of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase. In conclusion, theacrine alleviated experimental LF in rats by lowering cholesterol storage and decreasing cholesterol-related HSC activation. A plausible mechanism of theacrine on cholesterol metabolism may involve activation of SIRT3-FXR signaling pathway followed by decreased intestinal cholesterol absorption. [Display omitted] •Theacrine ameliorates experimental liver fibrosis in rats.•Theacrine reduces hepatic stellate cell activation-related protein expression.•Theacrine reduces hepatic cholesterol by activating Sirtuin 3-farnesoid X receptor signaling pathway.