Effect of the flaxseed lignan, secoisolariciresinol diglucoside, and its aglycone on cholesterol parameters in a rat model

Cardiovascular disease (CVD) is the leading cause of mortality in Canada, accounting for 37% of all deaths. Hypercholesterolemia, specifically increased low-density lipoprotein cholesterol (LDL-C) levels, is one of the major independent risk factors for CVD. Therapeutic interventions designed to lower serum lipid levels may decrease the risk of CVD; however current therapies are not sufficient to reach the lipid levels set by the National Cholesterol Education Plan. Attainment of optimal cholesterol levels in all patients will require new therapeutic agents with novel mechanisms of action. Flaxseed consumption is associated with broad spectrum health benefits, including reduction in blood cholesterol. This effect may relate to flaxseed's high lignan content, since the flaxseed lignan, secoisolariciresinol diglucoside (SDG), caused marked hypocholesterolemic effects in hypercholesterolemic rabbits. Further assessment of the hypocholesterolemic effects of SDG and its' aglycone, secoisolariciresinol (SECO), and their mechanisms of action may lead to a flax associated health claim or development of a nutraceutical product for treatment of hypercholesterolemia. My thesis aims to determine whether the flaxseed lignans, SDG and SECO, improve cholesterol homeostasis parameters in normo- and hypercholesterolemic rat models through alterations in the transcriptional regulation of enzymes and proteins in cholesterol metabolism. Female Wistar rats were randomly assigned to a standard or 1% cholesterol diet. Following a one week acclimatization period on the diets (18 rats per diet, 36 rats per lignan), groups of six rats (6 groups per lignan) were randomly assigned to one of three treatment groups (0, 4.4 or 8.8 µmol SDG or SECO/kg body weight). Lignan or vehicle (saline for SDG; 50:50 saline:polyethylene glycol for SECO) was administered daily by oral gavage. After four weeks, body and liver weights were recorded, serum lipids were measured using enzymatic kits, hepatic fat accumulation was determined by histochemical analysis and hepatic mRNA expression of cholesterol pathway targets was evaluated using real-time RT-PCR. Selected genes included transcription factors, cholesterol metabolic enzymes and proteins involved in cholesterol uptake and excretion. SDG significantly induced ACAT2 expression 54 and 66% in hypercholesterolen1ic rats treated with 4.4 and 8.8 µmol/kg, while SECO (8.8 µmol/kg) caused a significant reduction in CYP7A1 (71%) and a marked reduction in SREBP-2 (22%) expression levels in hypercholesterolemic rats. We observed marked dose-response reductions in total cholesterol and LDL-C in hypercholesterolemic rats treated with SDG and SECO. In addition, marked dose-response reductions in the LDL-C/high density lipoprotein cholesterol ratio were observed in hypercholesterolemic rats treated with SECO. Marked reductions in hepatic parenchymal lipid accumulation were observed in hypercholesterolemic rats treated with SDG and SECO, in addition to decreased liver weights and improved body condition. The present study indicates SDG and SECO administration alters cholesterol metabolism; however, their mechanism(s) of action remains unidentified and requires additional investigation. Furthermore, the present study identifies the flaxseed lignans, SDG and SECO, as the bioactive component involved in the hypocholesterolemic effects observed with flaxseed consumption in humans. Future studies are required to elucidate the mechanisms of action, which would contribute to the development of a flax-associated health claim or the development of a nutraceutical hypocholesterolemic agent