Metabolism. 2014 Apr; 63(4):593-601.

Scopoletin prevents alcohol-induced hepatic lipid accumulation by modulating the AMPK–SREBP pathway in diet-induced obese mice.

Lee HI1, Yun KW2, Seo KI1, Kim MJ3, Lee MK1.

1Department of Food and Nutrition, Sunchon National University, Suncheon, 540-950, South Korea.

2Department of Oriental Medicine Resources, Sunchon National University, Suncheon, 540-950, South Korea.

3Department of Hotel Cuisine, Suseong College, Daegu, 706-711, South Korea.



OBJECTIVE: This study investigated the effects of scopoletin on alcohol-induced hepatic lipid accumulation in diet-induced obese mice and its mechanism.

MATERIAL/METHODS: Alcohol (25% v/v, 5g/kg body weight) was orally administered once a day for 6 weeks to mice fed with a high-fat diet (35%kcal) with or without scopoletin (0.05%, wt/wt).

RESULTS: Scopoletin reduced plasma acetaldehyde, fatty acid, total cholesterol, triglyceride and insulin levels, hepatic lipid and droplets and fasting blood glucose levels that were increased by alcohol. Scopoletin significantly activated hepatic AMPK and inhibited ACC and SREBP-1c and the activities of lipogenic enzymes, such as FAS, PAP and G6PD compared to the alcohol control group. Moreover, scopoletin significantly inhibited hepatic CYP2E1 activity and protein levels but elevated the activities of SOD, CAT, GSH-Px and GST and the levels of GSH compared to the alcohol control group. The hepatic lipid peroxide level was significantly lowered by scopoletin supplementation in alcohol-administered obese mice.

CONCLUSIONS: Taken together, these results suggested that scopoletin can ameliorate alcohol-induced hepatic lipid accumulation by modulating AMPK-SREBP pathway-mediated lipogenesis in mice fed a high-fat diet.

PMID: 24559844



Alcoholic liver disease (ALD) is associated with a complex and multifaceted pathological process, which involves alcohol metabolism and secondary mechanisms, such as oxidative stress, inflammation and excessive fatty acid synthesis (1, 2). Alcoholic steatosis is the earliest stage of ALD and is characterized by hepatic fat accumulation (3). The present study showed that chronic administration (25%, 5 g/kg body weight) of alcohol to mice fed a high-fat diet dramatically increased hepatic and plasma triglyceride concentrations, which corresponded to an increase in the number of fat droplets in the hepatocytes, indicating that the administration of alcohol to obese mice aggravated hepatic lipid accumulation. However, scopoletin (0.05%, wt/wt) effectively attenuated alcohol-induced hepatic steatosis in high-fat diet-induced obese mice by inhibiting lipogenesis through modulation of the AMPK–SREBP signaling pathway. Moreover, the hepatoprotective effects of scopoletin may be mediated by inhibition of CYP2E1 activity and enhancement of the antioxidant defense system. The results of this study suggest that scopoletin may be a useful natural agent for the treatment or prevention of alcoholic fatty liver disease.

Figure 1Figure 1. The proposed possible mechanisms of scopoletin for hepatosteatotsis in alcohol-administered obese mice. The scopoletin supplementation elevated hepatic AMPK expression, which led to down-regulate hepatic ACC and SREBP-1c. Decreased SREBP-1c by scopoletin inactivated lipogenic enzymes (FAS, PAP and G6PD), resulting in decrease in hepatic lipid accumulation. Also, scopoletin enhanced alcohol metabolic enzyme activities (ADH and ALDH2) and suppressed protein expression and enzyme activity of CYP2E1, which led to reduce plasma acetaldehyde and hepatic lipid peroxide levels and increase antioxidant defense system, such as SOD, CAT, GSH-Px, GST and GSH. ACC: acetyl-CoA carboxylase, ADH: alcohol dehydrogenase, ALDH2: aldehyde dehydrogenase 2, AMPK: AMP-activate protein kinase, CAT: catalase, CYP2E1: cytochrome P4502E1, FAS: fatty acid synthase, GSH: glutathione, GSH-Px: glutathione peroxidase, GST: glutathione-S-transferase, G6PD: glucose-6-phosphatate dehydrogenase, PAP: phosphatidate phosphohydrolase, SOD: superoxide dismutase, SREBP-1c: sterol regulatory element-binding proteins-1c.



  1. Ding RB, Tian K, Huang LL, et al. Herbal medicines for the prevention of alcoholic liver disease: a review. J Ethnopharmacol 2012; 144: 457–65.
  2. Seth D, Haber PS, Syn WK, et al. Pathogenesis of alcohol induced liver disease: classical concepts and recent advances. J Gastroenterol Hepatol 2011; 26: 1089–105.
  3. Newton BW, Russell WK, Russell DH, et al. Liver proteome analysis in a rodent model of alcoholic steatosis. J Proteome Res 2009; 8: 1663–71.

Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2012R1A1A2041931).



Mi-Kyung Lee, Ph.D.

Department of Food and Nutrition,

Sunchon National University,

255 Jungang-ro, Suncheon, Jeonnam, 540-950, Korea.

TEL.: +82-61-750-3656, Fax : +82-61-752-3657



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