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Title: Changes in cholesterol homeostasis modify the response of F1B hamsters to dietary very long chain n-3 and n-6 polyunsaturated fatty acids

Author
item LECKER, JAIME - The Biomedical Research Centre
item MATTHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item BILLHEIMER, JEFFREY - University Of Pennsylvania
item RADER, DANIEL - University Of Pennsylvania
item LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Lipids in Health and Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2011
Publication Date: 10/21/2011
Citation: Lecker, J.L., Matthan, N.R., Billheimer, J.T., Rader, D.J., Lichtenstein, A.H. 2011. Changes in cholesterol homeostasis modify the response of F1B hamsters to dietary very long chain n-3 and n-6 polyunsaturated fatty acids. Lipids in Health and Disease. 186:1-10.

Interpretive Summary: The hamster is frequently used as an animal model to study the effects of diet on the development of atherosclerosis. Omega-3 fatty acids have been demonstrated to decrease heart disease risk in humans. The aims of this study were to determine the mechanism by which omega-3 fatty acids decrease atherosclerotic lesion formation. Hamsters were fed diets containing fish oil, rich in omega-3 fatty acids, or safflower oil, poor in omega-3 fatty acids, both coupled either with high levels of dietary cholesterol (cholesterol-supplemented) or low levels of dietary cholesterol plus a cholesterol lowering drug (lovastatin) (cholesterol-depleted). Cholesterol-supplemented hamsters fed fish oil, relative to safflower oil, had higher non-high density lipoprotein cholesterol and triglyceride concentrations. This observation is paradoxical to that expected on the basis of what has been reported in humans. These plasma lipid concentrations were associated with lower levels of genes that uptake cholesterol from plasma into the liver and higher levels of genes that are involved in transporting cholesterol out of the liver. In contrast, cholesterol-depleted hamsters fed fish oil, relative to safflower oil, had lower non- high density lipoprotein cholesterol and triglyceride concentrations that were associated with lower genes that uptake plasma cholesterol into the liver but not genes that transport cholesterol out of the liver. These data suggest disturbing cholesterol homeostasis in hamsters alters their response to dietary fat, which is reflected in altered plasma lipoprotein patterns and regulation of genes associated with their metabolism. These data also suggest that the hamster is not an appropriate animal model in which to study diet induced atherosclerosis.

Technical Abstract: The plasma lipoprotein response of F1B Golden-Syrian hamsters fed diets high in very long chain (VLC) n-3 PUFA is paradoxical to that observed in humans. This anomaly is attributed, in part, to low lipoprotein lipase activity and dependent on cholesterol status. To further elucidate the mechanism(s) for these responses, hamsters were fed diets containing supplemental fish oil (VLC n-3 PUFA) or safflower oil (n-6 PUFA) (both 10% [w/w]) and were either cholesterol-supplemented (0.1% cholesterol [w/w]) or cholesterol-depleted (0.01% cholesterol [w/w] and 10 days prior to killing fed 0.15% lovastatin+2% cholestyramine [w/w]). Cholesterol-supplemented hamsters fed fish oil, relative to safflower oil, had higher non-HDL cholesterol and triglyceride concentrations (P<0.001) which were associated with lower hepatic LDL receptor, sterol regulatory element binding protein (SREBP)-1 and acyl-CoA: cholesterol acyl transferase-2 (ACAT) mRNA and protein levels (p<0.05), and higher hepatic apolipoprotein (apo) B-100 and apo E protein levels. In contrast, cholesterol-depleted hamsters fed fish oil, relative to safflower oil, had lower non-HDL cholesterol and triglyceride concentrations (P<0.001) which were associated with lower hepatic SREBP-1c (p<0.05) and no differences in apo B-100, apo E or ACAT-2 mRNA or protein levels. Independent of cholesterol status, hamsters fed fish oil, relative to safflower oil, had lower HDL cholesterol concentrations (p<0.001), which were associated with lower hepatic apoA-I protein levels (p<0.05). These data suggest that disturbing cholesterol homeostasis in F1B hamsters alters their response to dietary fatty acids, which is reflected in altered plasma lipoprotein patterns and regulation of genes associated with their metabolism.