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 Chinesemedicine Chuanxiong, has been clinically approved for treatingischemic cardio-cerebrovascular diseases and has shown protectiveeffects against liver injury. However, its regulatory effect onhepatic fatty acid β-oxidation in nonalcoholic fatty liver disease(NAFLD) mice is not fully understood. In this study, an NAFLDmice model was established using high-fat diet (HFD), and TMPwas administrated to the mice. Levels of triglyceride (TG), totalcholesterol, alanine aminotransferase (ALT) and aspartateaminotransferase (AST) were measured to assess the hepatic steatosisand liver function. HepG2 cells were treated with free fatty acids toinduce lipid accumulation, oxidative stress and mitochondriadamage. The expression levels of long-chain acyl-CoAdehydrogenase (LCAD), cyclin-dependent kinase 1(CDK1) andsirtuin 3 (SIRT3) were analyzed using Western blot. TMP treatmentalleviated FFA-induced lipids accumulation and reduced oxidativestress and cellular injury. TMP significantly decreased cholesteroland 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.