Effect of the flaxseed lignan, secoisolariciresinol diglucoside, and its aglycone on cholesterol parameters in a rat model
Date
2006
Authors
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Publisher
ORCID
Type
Degree Level
Masters
Abstract
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.
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Degree
Master of Science (M.Sc.)
Department
College of Pharmacy and Nutrition
Program
College of Pharmacy and Nutrition