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Flaxseed Reduces Plasma Cholesterol Levels in Hypercholesterolemic Mouse Models

Institute for Translational Medicine and Therapeutics (M.A.P., J.T.B., L.T.B., P.O.S., D.J.R.)
Division of General Internal Medicine, General Clinical Research Center University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (P.O.S., L.T.B.)

Address correspondence to: Daniel J. Rader, M.D., Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, 421 Curie Blvd., BRB II/III, Philadelphia, PA 19104-6160. E-mail: rader{at}mail.med.upenn.edu

Objective: We examined the effects of whole ground flaxseed added to a Western diet on plasma and hepatic lipids and hepatic gene expression in male and female human apolipoprotein B-100 transgenic (hApoBtg) mice which have a plasma lipid profile more closely resembling man than wild type mice and in mice lacking the low density lipoprotein receptor (LDLr) and apolipoprotein B mRNA editing enzyme complex 1 (LDLr^–/–/apobec^–/–).

Methods: The Westernized control diet containing 0.1% cholesterol and 30% kcal as fat was fed for 10 days to hApoBtg mice and for 14 days to LDLr^–/–/apobec^–/– mice. Animals from each genetic background were then divided into 2 groups based on gender and mean plasma total cholesterol (TC). The hApoBtg and LDLr^–/–/apobec^–/– mice either continued on the control diet for a total of 31 and 35 days, respectively or were fed 20% w/w whole ground flaxseed (flax) with comparable caloric, macronutrient and fiber content for 21 days. Blood was obtained after a 4 hour fast from all mice prior to feeding both control and flax diets, after 10 days on the flax diet, and after 21 days on the flax at which time all mice were exsanguinated.

Results: The control diet increased TC by >100 mg/dl in the hApoBtg with a greater increase observed in males and by 800 mg/dl in mice lacking the LDLr. After 3 weeks, the flax diet significantly reduced plasma TC by 19% and 22% in hApoBtg and LDLr^–/–/apobec^–/–, respectively and non-high density lipoprotein cholesterol (non-HDL-C) by 24% in both models (p for all <0.05). Flax significantly reduced hepatic cholesterol in hApoBtg by 32% and 47% in males and females, respectively and LDLr^–/–/apobec^–/– mice by 66%. Flax had no effect on the expression of the following hepatic genes: LDLr, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, phospholipid transfer protein, cholesterol 7 hydroxylase, fatty acid synthase, and acyl CoA oxidase in either mouse model.

Conclusions: Flaxseed reduces plasma and hepatic cholesterol in hApoBtg mice, but had no effect on hepatic lipogenic genes and was equally effective in mice lacking LDLr. The combined data suggest that the lipid lowering effect of flax is not hepatic mediated and may be at the level of cholesterol absorption and/or bile acid reabsorption.