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ETHNOPHARMACOLOGICAL RELEVANCE Polygoni Multiflori Radix (PMR) and Polygoni Multiflori Radix Praeparata (PMRP) that is used after processing are two well-known traditional Chinese medicines. PMRP is traditionally reported to have lipid-reducing activity as recorded in Chinese Pharmacopoeia. AIM OF THE STUDY This study aims to observe the alleviation of Polygoni Multiflori Radix Praeparata water extract (PMRPWE) and Polygoni Multiflori Radix water extract (PMRWE) against nonalcoholic fatty liver disease (NAFLD), and its potential engaged mechanism and the main active ingredients. MATERIALS AND METHODS The contents of 2,3,5,4'-tetrahydroxy-stilbene-2-O-β- D-glucoside (TSG), emodin and physcion in PMRWE and PMRPWE were measured by using high-performance liquid chromatography (HPLC). NAFLD was induced in rats by high-fat diet (HFD) feeding for 8 weeks. At the same time, rats were orally given with PMRWE (70, 140, 280 mg/kg) or PMRPWE (70, 140, 280 mg/kg) every day. Serum and liver biochemical parameters, hepatic gene expression and enzymatic activity were detected. Cellular lipids accumulation in human normal liver L-02 cells was induced by 0.5 mM non-esterified fatty acid (NEFA). RESULTS The results of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver reactive oxygen species (ROS) and hematoxylin-eosin (H&E) observation showed that PMRWE and PMRPWE both alleviated liver injury in HFD-fed rats. The results of liver triglyceride (TG), total cholesterol (TC) and NEFA amounts, and liver Oil Red O staining evaluation showed that PMRWE and PMRPWE both reduced hepatic lipids accumulation in HFD-fed rats. The results of 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorescence staining and cellular TG content showed that both PMRWE and PMRPWE reduced NEFA-induced cellular lipids accumulation in L-02 cells. PMRWE and PMRPWE increased liver mRNA expression of some signals involved in mitochondrial β oxidation, including the key enzyme carnitine palmitoyltransferase 1A (CPT1A). Moreover, PMRWE and PMRPWE increased the decreased liver CPT1A enzymatic activity in HFD-fed rats. Etomoxir (ETO), a CPT1A inhibitor, weakened the lipid-lowering activity of PMRWE and PMRPWE in vitro. Additionally, the main compounds in PMRWE and PMRPWE including TSG, emodin, physcion and resveratrol all reduced cellular lipids accumulation induced by NEFA in L-02 cells. CONCLUSIONS PMRWE and PMRPWE alleviated NAFLD through promoting mitochondrial β oxidation by enhancing liver CPT1A activity. Stilbenes (including TSG, polydatin and resveratrol) and anthraquinones (including physcion, emodin and rhein) may be the main active compounds contributing to the lipid-lowering activity provided by PMRWE and PMRPWE.