Fatty liver is caused by sedentary lifestyle, diet enriched with cholesterol and saturated fats, and medical conditions. Lifestyle contributors include obesity, deprivation of physical exercise, and excessive alcohol consumption [21
]. In the present study, feeding with HFC diet for 8 or 15 days markedly increased serum TC, hepatic TG and TC levels in mice, with the extent of elevation for hepatic TG being more prominent. Serum TG level was slightly increased in mice fed with HFC diet for 8 but not 15 days. The animal model used in the present study therefore mimics the clinical condition of fatty liver rather than hyperlipidemia. In most instances, the treatment of fatty liver requires a proper control of the underlying abnormal conditions, including high blood TG level, diabetes, excessive alcohol intake and obesity [22
]. At present, orthodox medicine has no specific drug treatment to reverse a condition of fatty liver. Moreover, most of the synthetic lipid-lowering drugs can lead to various adverse reactions, even though they can alleviate the condition of hepatic steatosis. As such, the World Health Organization has adopted a policy in favor for development of herbal remedies for the clinical management of hepatic steatosis.
The acute treatment with EtFSC increased the serum TG level and at the same time, decreased hepatic TC level in normal mice. As expected, the hypertriglyceridemic action of EtFSC is suppressed by the co-administration of fenofibrate (data not shown). Fenofibrate, a broad-spectrum lipid-lowering drug of the fibrate class, inhibits the synthesis of cholesterol and triglycerides as well as enhances their elimination [23
]. In the present study, it was found that both fenofibrate and EtFSC treatment for 7 days reduced the serum TG level but elevated the serum TC levels in HFC diet-induced hypercholesterolemic mice. The blood TG lowering effect may be related to the high blood TC levels in HFC diet-fed mice. Possibly, hypercholesterolemia may facilitate the utilization of or inhibit the synthesis of TG. The fenofibrate- or EtFSC-induced increase in serum TC levels may result from the secretion of hepatic TC into the blood stream. While fenofibrate did not reduce hepatic TC levels in mice fed with HFC diet for 8 days, it lowered hepatic TC in mice fed with HFC diet for 15 days. This observation may be due to a higher content of hepatic TC in mice fed with HFC diet for 15 days than those fed with HFC diet for 8 days.
It has been reported that the hypolipidemic action of fenofibrate is attributed to the stimulation of lipolysis and the elimination of TG-rich particles from plasma through activating lipoprotein lipase and reducing the production of apolipoprotein C-III, as well as inducing enzymes for catalyzing β
-oxidation of fatty acid in mitochondria [25
]. In addition, fenofibrate also reduces intestinal cholesterol absorption [28
]. Therefore, the mechanism involved in the reduction of hepatic TG level in hypercholesterolemic mice by EtFSC treatment may also be due to its effect on the lipoprotein lipase, apolipoprotein C-III, β
-oxidation, or/and cholesterol absorption. The detail mechanism of action remains to be elucidated. In our previous study, the treatment of schisandrin B, bifendate (synthetic intermediate of schisandrin C) and bicyclol (synthetic dibenzocyclooctadiene derivative) [16
] produced a significant hepatotrophic effect, but EtFSC treatment only slightly increased the hepatic index in hypercholesterolemic mice. The lesser degree of liver hypertrophy caused by EtFSC than purified active principles including schisandrin B, bifendate, and bicyclol and fenofibrate, and the relatively low toxicity might make EtFSC a desirable candidate herbal preparation for the treatment of fatty liver.
Peroxisome proliferator-activated receptors (PPARs) play important roles in the regulation of lipid metabolism involved in inflammation, energy balance, atherosclerosis and non-alcoholic fatty liver disease [29
]. Fenofibrate, an agonist of PPARα
, is a useful therapeutic option for patients with dyslipidemias, particularly those associated with diabetes mellitus or coronary heart disease, and metabolic syndrome [32
]. EtFSC may activate PPARs and thereby suppress the lipid accumulation in the liver ().
Hypothetical action of EtFSC in lowering liver lipid content through the intermedicacy of PPARs.
In conclusion, EtFSC treatment could prevent or ameliorate the degree of liver steatosis in hypercholesterolemic mice. While fenofibrate produced a more potent lipid-lowering action than that of EtFSC, it caused a larger extent of liver hypertrophy. Taken together with the relatively low toxicity, EtFSC may be used clinically for the management of fatty liver disease [34