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.

Our aim was to study whether the absence of apolipoprotein (apo) C3, a strong inhibitor of lipoprotein lipase (LPL), accelerates the development of obesity and consequently insulin resistance. Apoc3 ؊/؊ mice and wild-type littermates were fed a high-fat (46 energy %) diet for 20 weeks. After 20 weeks of high-fat feeding, apoc3؊/؊ mice showed decreased plasma triglyceride levels (0.11 ؎ 0.02 vs. 0.29 ؎ 0.04 mmol, P < 0.05) and were more obese (42.8 ؎ 3.2 vs. 35.2 ؎ 3.3 g; P < 0.05) compared with wild-type littermates. This increase in body weight was entirely explained by increased body lipid mass (16.2 ؎ 5.9 vs. 10.0 ؎ 1.8 g; P < 0.05). LPL-dependent uptake of triglyceride-derived fatty acids by adipose tissue was significantly higher in apoc3 ؊/؊ mice. LPL-independent uptake of albuminbound fatty acids did not differ. It is interesting that whole-body insulin sensitivity using hyperinsulinemiceuglycemic clamps was decreased by 43% and that suppression of endogenous glucose production was decreased by 25% in apoc3 ؊/؊ mice compared with control mice. Absence of apoC3, the natural LPL inhibitor, enhances fatty acid uptake from plasma triglycerides in adipose tissue, which leads to higher susceptibility to diet-induced obesity followed by more severe development of insulin resistance. Therefore, apoC3 is a potential target for treatment of obesity and insulin resistance. Diabetes 54:664 -671, 2005

Sphingolipids lower plasma cholesterol and triacylglycerol and protect the liver from fat- and cholesterol-induced steatosis.

Sphingolipids lower plasma cholesterol and triacylglycerol and protect the liver from fat- and cholesterol-induced steatosis.

Hepatic VLDL and glucose production is enhanced in type 2 diabetes and associated with hepatic steatosis. Whether the derangements in hepatic metabolism are attributable to steatosis or to the increased availability of FA metabolites is not known. We used methyl palmoxirate (MP), an inhibitor of carnitine palmitoyl transferase I, to acutely inhibit hepatic FA oxidation and investigated whether the FAs were rerouted into VLDL secretion and whether this would affect hepatic glucose production. After an overnight fast, male APOE3*Leiden transgenic mice received an oral dose of 10 mg/kg MP. Administration of MP led to an 83% reduction in plasma ␤ -hydroxybutyrate (ketone body) levels compared with vehicle-treated mice (0.47 ؎ 0.07 vs. 2.81 ؎ 0.16 mmol/l, respectively; P Ͻ 0.01), indicative of impaired ketogenesis. Plasma FFA levels were increased by 32% and cholesterol and insulin levels were decreased by 17% and 50%, respectively, in MP-treated mice compared with controls. MP treatment led to a 30% increase in liver triglyceride (TG) content. Surprisingly, no effect on hepatic VLDL-TG production was observed between the groups at 8 h after MP administration. In addition, the capacity of insulin to suppress endogenous glucose production was unaffected in MP-treated mice compared with controls.In conclusion, acute inhibition of FA oxidation increases hepatic lipid content but does not stimulate hepatic VLDL secretion or reduce insulin sensitivity. Hepatic VLDL-triglyceride (TG) secretion is an important determinant of plasma lipid levels. The rate of VLDL secretion is generally believed to be substrate-driven (i.e., the hepatic content of TG and FA determines VLDL assembly and the rate of VLDL secretion) (1-3). Indeed, addition of FA to hepatocytes in vitro leads to increased hepatic TG and eventually to enhanced VLDL secretion (4). However, the hypothesis that VLDL secretion is substratedriven in vivo has not been proven.Hepatic TG content is the result of uptake and synthesis on the one hand and ␤ -oxidation and VLDL-TG secretion on the other. The importance of ␤ -oxidation is illustrated by the severe phenotype of humans and mice with impaired ␤ -oxidation. Deficiency in hepatic ␤ -oxidation enzymes results in severe plasma hypoketosis and fatty liver (5, 6). In ␤ -oxidation, the rate-limiting enzyme is carnitine palmitoyl transferase 1 (CPT1), which couples long-chain FAs to carnitine for transportation into the mitochondria (7,8). Methyl palmoxirate (MP) is a specific and irreversible inhibitor of CPT1 and thereby inhibits ␤ -oxidation (9, 10).In this study, we tested the effect of acute inhibition of ␤ -oxidation in vivo by MP on hepatic VLDL production in fasted hyperlipidemic APOE3*Leiden transgenic mice.Abbreviations: acc1 , acetyl-coenzyme A carboxylase 1; apoB, apolipoprotein B; CPT1, carnitine palmitoyl transferase 1; dgat , acyl:diacylglycerol transferase; fas , fatty acid synthase; ␤ -HB, ␤ -hydroxybutyrate; hmgs , 3-hydroxy-3-methylglutaryl-coenzyme A synthase; mcad , mediumchain acyl coenzyme...