Abstract

TETRAMETHYLPYRAZINE AMELIORATES HEPATIC STEATOSIS BY PROMOTING MITOCHONDRIAL ?-OXIDATION VIA CDK1/SIRT3/LCAD PATHWAY IN MICE

Xueying Jin, Sijie Wang, Liu Tao, Yuping Wang, Xiaomin Yao*, Pei Yu* and
Luchen Shan*

ABSTRACT

Tetramethylpyrazine (TMP), a major active component of Chinese
medicine Chuanxiong, has been clinically approved for treating
ischemic cardio-cerebrovascular diseases and has shown protective
effects against liver injury. However, its regulatory effect on
hepatic fatty acid β-oxidation in nonalcoholic fatty liver disease
(NAFLD) mice is not fully understood. In this study, an NAFLD
mice model was established using high-fat diet (HFD), and TMP
was administrated to the mice. Levels of triglyceride (TG), total
cholesterol, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) were measured to assess the hepatic steatosis
and liver function. HepG2 cells were treated with free fatty acids to
induce lipid accumulation, oxidative stress and mitochondria
damage. The expression levels of long-chain acyl-CoA
dehydrogenase (LCAD), cyclin-dependent kinase 1(CDK1) and
sirtuin 3 (SIRT3) were analyzed using Western blot. TMP treatment
alleviated FFA-induced lipids accumulation and reduced oxidative
stress and cellular injury. TMP significantly decreased cholesterol
and triglyceride levels, reduced lipid peroxidation and improved liver function in NAFLD mice. TMP alleviated FFA-induced mitochondria damage in hepatic cells and upregulated the expression of CDK1, SIRT3 and deacetylation of LCAD in mitochondria. These findings suggested that TMP alleviated lipid deposition in hepatic cells by regulating the homeostasis of mitochondria and promoting the fatty acid β-oxidation via activation of CDK1/SIRT3/LCAD pathway, making it a promising therapeutic drug for NAFLD.

Keywords: Tetramethylpyrazine; NAFLD; mitochondrial fatty acid ?-oxidation; CDK1/SIRT3/LCAD pathway.