Response of apolipoprotein E*3‐Leiden transgenic mice to dietary fatty acids: combining liver proteomics with physiological data

Abstract

Dietary fatty acids have a profound impact on atherosclerosis, but mechanisms are not fully understood. We studied the effects of a saturated fat diet supplemented with fish oil, trans10,cis12 conjugated linoleic acid (CLA), or elaidic acid on lipid and glucose metabolism and liver protein levels of APOE*3 Leiden transgenic mice, a model for lipid metabolism and atherosclerosis. Fish oil lowered plasma and liver cholesterol and triglycerides, plasma free fatty acids, and glucose but increased plasma insulin. CLA lowered plasma cholesterol but increased plasma and liver triglycerides, plasma beta-hydroxybutyrate, and insulin. Elaidic acid lowered plasma and liver cholesterol. Proteomics identified significant regulation of 65 cytosolic and 8-membrane proteins. Many of these proteins were related to lipid and glucose metabolism, and to oxidative stress. Principal component analysis revealed that fish oil had a major impact on cytosolic proteins, and elaidic acid on membrane proteins. Correlation analysis between physiological and protein data revealed novel clusters of correlated variables, among which a metabolic syndrome cluster. The combination of proteomics and physiology gave new insights in mechanisms by which these dietary fatty acids regulate lipid metabolism and related pathways, for example, by altering protein levels of long-chain acyl-CoA thioester hydrolase and adipophilin in the liver.

Dietary fatty acids affecting hepatic metabolism and atherosclerosis – mechanisms unravelled using a proteomics approach

“…The suspected increase in ␤-oxidation rates would explain the lower levels of plasma triglycerides and free fatty acids as well as hepatic triglycerides in the mice after fish oil consumption. The increase in ␤-oxidation caused by trans10, cis12 CLA consumption was however indicative of the development of insulin resistance, since levels of plasma and hepatic triglycerides, as well as plasma ␤-hydroxybutyrate and plasma insulin were significantly increased (de Roos et al, 2005a).…”

“…How various dietary fatty acids can differentially affect hepatic protein expression became clear when we compared the effects of three dietary fatty acids -fish oil, trans10,cis12 CLA and elaidic acid -on plasma and liver metabolites and hepatic proteins in ApoE*3-Leiden transgenic mice (de Roos et al, 2005a). These mice are a model for lipid metabolism, insulin resistance and atherosclerosis that are sensitive to changes in many components of the diet (van Vlijmen et al, 1994;van Vlijmen et al, 1996;van Vlijmen et al, 1998).…”

“…Significant changes were detected in pathways involved with glucose and lipid metabolism.This was consistent with the physiological changes that occurred in response to the diets. For example, fish oil, and also trans10, cis12 CLA, increased hepatic catalase and long chain acyl-CoA thioester hydrolase proteins, indicative of an increased ␤-oxidation rate (de Roos et al, 2005a). Long chain acyl-CoA thioester hydrolase expression had never been linked to specific dietary fatty acid treatments before.…”

Symbiosis of chemometrics and metabolomics: past, present, and future

“…Suppose that the APOE3-Leiden mice are fed with different fat levels in their nutrition [81,82]. Upon these different levels, they develop atherosclerosis in a severity related to some extent to the fat load.…”

Inter-organ proteomic analysis reveals insights into the molecular mechanisms underlying the anti-diabetic effects of cis-9, trans-11 conjugated linoleic acid in ob/ob mice

“…Both CLA-rich diets contained 0.6% (w/w) cis-9 trans-11 CLA. Fasting plasma biomarkers of insulin sensitivity were measured and changes in protein expression in skeletal muscle, hepatic and epididymal adipose tissues were determined using two-dimensional gel electrophoresis and MS (2) .The CLA-fed mice were equally protected from the metabolic syndrome compared with the control, as shown by significant decreases of 30-50 % in plasma insulin (P < 0.05), glucose (P < 0.05), NEFA (P < 0.05), TAG (P < 0.05) and IL-6 (P < 0.05) and an increase of 34 % in plasma adiponectin (P < 0.05). Proteomic analysis indicated that 134, ninety-two and forty-three proteins, including post-translationally modified isoforms, were significantly altered (P < 0.05) in the skeletal muscle, hepatic and adipose tissues respectively of CLA-fed mice.…”