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

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

  • Chem Biol Interact. 2022 Sep 1;364:110051. doi: 10.1016/j.cbi.2022.110051.
Xi-Ting Lv 1 Ruo-Hong Wang 1 Xiao-Ting Liu 1 Yu-Jing Ye 1 Xin-Yu Liu 1 Jing-Da Qiao 2 Guo-En Wang 3
Affiliations

Affiliations

  • 1 School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
  • 2 Institute of Neuroscience and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
  • 3 School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China. Electronic address: wangge07@126.com.
Abstract

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.

Keywords

Carbon tetrachloride; Cholesterol 7α-hydroxylase; Hepatic stellate cell; Stearoyl-CoA desaturase-1; Sterol 12α-hydroxylase.

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