Hyperlipidemia, which can be broadly categorized into hypercholesterolemia, hypertriglyceridemia and mixed hyperlipidemia, is causally related to the pathogenesis of CHD, cerebrovascular diseases, peripheral vascular disease and pancreatitis[18–21]. One major cause hyperlipidemia is unhealthy eating habit. In the present study, both serum and hepatic lipid levels were notably elevated in mice fed with HFCBD, a high-fat diet used in the experiment. Although HDL levels are regulated by cholesteryl ester transfer protein, hepatic TG lipase and lipoprotein lipase etc., the increased HDL and LDL levels may be an event secondary to hypercholesterolemia induced by feeding HFCBD in mice. In this connection, Guay et al. found that the cholesterol-elevating effect of a high-fat diet was associated with the formation of larger LDL particles than those of a low-fat diet. It is well known that LDL is formed from very LDL (VLDL) which secretes from liver and allows the supply of triglycerides to tissues. However, it is not clear as to why feeding mice with HFCBD resulted in low serum TG levels[14–16, 23]. Lipogenic activity appears to be up-regulated in obese condition and serum triglyceride is consumed for lipid synthesis, so serum TG decreased, but the obese did not found in the mice fed with a high-fat diet. In clinical situation, blood TG levels in patients with hypercholesterolemia are not lower than those of normal individuals. Therefore, the mouse model of hypercholesterolemia, as adopted in the present study, may be different from hypercholesterolemia in human patients in the pathogenesis of the disease state. The apparent liver injury induced by feeding HFCBD is likely related to the accumulation of fat in hepatic tissue[24, 25]. In addition, hyperlipidemia is usually concerned hyperglycemia and hyperinsulinemia caused by insulin resistance in clinic, but in the present study, serum glucose levels were no significant differences between model group and normal mice (data not shown). This may be related to the short-time modeling (13 days).
Fenofibrate, a fibric acid derivative, is used to treat severe hypertriglyceridemia and mixed dyslipidemia (i.e., increases both TC and TG levels in blood) in patients who did not respond to non-pharmacological intervention, of which the condition is usually associated with an increased risk of atherosclerosis and/or fatty liver. Fenofibrate treatment was found to reduce serum TG and LDL levels, but increase HDL level in hyperlipidemic patients. In the present study, fenofibrate supplementation decreased serum TC, TG, and HDL levels in ND-fed mice. The reduction of HDL level by fenofibrate may result from the drug-induced reaction secondary to hypolipidemic action. In addition, liver injury and hepatomegaly induced or aggravated by fenofibrate treatment were observed in ND and HFCBD-fed mice. Although fenofibrate treatment improved the hepatic microcirculatory patency and oxygen availability in a high-fat diet-induced fatty liver in mice as well as suppressed the growth of human hepatocellular carcinoma cells in vitro, it caused DNA damage in rat livers and promoted hepatocarcinogenesis through increasing oxidative stress in rodents[30–33]. Furthermore the long-term and high-dose administration of fenofibrate caused liver damage and dysfunction in rodents[34–36]. Fenofibrate is available in a formulation of 100-mg tablet for oral use at a daily dose of 300 mg in adult patients (i.e., 5 mg/kg/day for 60 kg). The dose (180 mg/kg in ND-fed mice and 170 mg/kg in HFCBD-fed mice) adopted in the present study is about 35–fold higher than the human dose.
Despite recent advances in the understanding of hyperlipidemia and its associated adverse clinical outcomes, hyperlipidemia remains the major cause of morbidity and mortality throughout the world. While chemical drugs are potent in lowering lipid levels in blood, they also produce some side effects in patients who require life-long medication. Recently, a shift from drug therapy to dietary supplementation with naturally-occurring ingredients has become a trend in the management of hyperlipidemia and fatty liver disease. Medicinal plants have been used for over millennia and are highly esteemed all over the world as a rich source of therapeutic agents, food supplements and/or additives for the prevention and treatment of diseases. FSC, which is a commonly used Chinese herb, was tested in the mouse model of hypercholesterolemia. Although both AqFSC and EtFSC notably lowered hepatic TC and TG contents and elevated serum HDL and LDL levels in mice fed with HFCBD, no significant differences in serum lipid levels were observed in mice fed with normal diet supplemented with AqFSC and EtFSC. This suggested that the effect of FSC on lipids may be dependent on basal lipid levels in the body. Under normal conditions, FSC did not affect the serum lipid levels, but it exaggerated the elevation of serum HDL and LDL by HFCBD. It is well known that HDL and LDL are “good cholesterol” and “bad cholesterol” with respect to their role in the development of CHD[37–39]. Whether or not dietary FSC-induced increase in both HDL and LDL levels is “good” or “bad” remains to be investigated.
Both AqFSC and EtFSC alleviated the accumulation of lipids in livers of HFCB diet-fed mice, but only EtFSC suppressed the serum ALT activity, a biochemical index of liver damage. The inability of AqFSC to protect against liver damage in hypercholesterolemic mice may be related to the possibility that the anti-fatty liver ingredients, which are present in both AqFSC and EtFSC, are distinct from those for liver protection, with the latter being present in EtFSC only. As EtFSC also inhibited serum ALT activity in ND-fed mice, the direct inhibition of EtFSC on ALT activity cannot be excluded. The hepatoprotective effect of EtFSC can be confirmed by the measurement of alternative housekeeping enzymes like sorbitol dehydrogenase in the blood and/or histological analysis of liver tissue. Lignans are currently considered as hepatoprotective ingredients in FSC by virtue of their in vivo antioxidant potential[40, 41]. The fat-soluble lignans likely reside in EtFSC rather than AqFSC[42, 43]. Therefore lignans in FSC unlikely contribute to the amelioration of fatty liver induced by HFCBD. There are eight integrants in the water-soluble fraction of FSC through spectral analysis, they include protocatechuic acid, quinic acid, 2-methyl citrate, 5-hydroxymethyl-2-furancarboxaldehyde, zingerone glucoside, thymoquinol 2-glu-coside, thymoquinol 5-glucoside, daucosterol. EtFSC mainly contains lignans including schizandrin A, B, and C; schizandrol A and B; gomisin B, C, D, E, G, H, J, and N; tigloylgomisin H; and angeloylgomisin H etc..
Fenofibrate has been prescribed for patients with dyslipidemia in the US since 1998. The lipid-lowering action of fenofibrate in the blood (or likely in liver tissue too) has been shown to be mediated by the activation of PPAR-alpha and lipoprotein lipase, as well as suppression of apoliprotein C-III, fatty acid synthase, acetyl CoA carboxylase, and cholesterol absorption, etc.[46–49]. Recently, it is revealed that fenofibrate induces the activity of enzymes in the tricarboxylic acid cycle. It is unclear whether this may contribute to weight loss induced by fenofibrate. Although active ingredient of FSC (schisandrin B) and its related analogs (bifendate, and bicyclol) have been shown to affect lipid metabolism[51–54], the mechanism underlying the lipid-lowering effect of AqFSC and EtFSC remains to be elucidated.