Prolonged feeding of mice with conjugated linoleic acid increases hepatic fatty acid synthesis relative to oxidation.

Feeding mice conjugated linoleic acid (9 cis,11 trans/9 trans,11 cis-and 10 trans,12 cis-CLA in equal amounts) resulted in triacylglycerol accumulation in the liver. The objective of this study was to examine whether this steatosis is associated with changes in hepatic fatty acid synthesis and oxidation. Therefore, we measured the activities of key enzymes of fatty acid synthesis, i.e., acetyl-CoA carboxylase and fatty acid synthase and of fatty acid oxidation, i.e., 3-hydroxy-acyl-CoA dehydrogenase and citrate synthase in livers of mice fed a diet with 0.5% (w/w) CLA. CLA (a 1:1 mixture of the 10 trans, 12 cis and 9 cis, 11 trans isomers of octadecadenoic acid) was administered for 3 and 12 weeks with high-oleic sunflower oil fed as control. The proportion of body fat was significantly lower on the CLA than on the control diet and this effect was already significant after 3 weeks. The specific activites of 3-hydroxy-acyl-CoA dehydrogenase and citrate synthase were unaffected by CLA both after 3 and 12 weeks. The specific activity of fatty acid synthase was nonsignificantly raised (by 12%) after 3 weeks on the CLA diet but had increased significantly (by 34%) after 12 weeks of feeding. The specific activity of acetyl-CoA carboxylase had also increased both after 3 weeks (by 53%) and 12 weeks (by 23%) on the CLA diet, but this effect did not reach statistical significance. Due to CLA-induced hepatomegaly, the overall capacity for both fatty acid oxidation and synthesis-as evidenced by the total hepatic activities of 3-hydroxy-acyl-CoA dehydrogenase, citrate synthase, acetyl-CoA carboxylase, and fatty acid synthase-was significantly greater in the CLA-fed group after 12 weeks, although the overall capacity for fatty acid synthesis had increased more than that for fatty acid oxidation. Thus, this study indicates that prolonged, but not short-term, feeding mice with CLA increased hepatic fatty acid synthesis relative to oxidation, despite the decrease in body fat and the increase in liver weight seen earlier. It is concluded that the observed CLA-induced changes in hepatic fatty acid synthesis and oxidation are the result, rather than the cause, of the lowering of body fat.

Cholesterol and copper in the liver of rabbit inbred strains with differences in dietary cholesterol response.

In order to investigate whether cholesterol intake influences the hepatic copper content of rabbits, we compared the hepatic copper content of two rabbit inbred strains after feeding the animals a control or a cholesterol-rich diet. One strain was not reactive to dietary cholesterol (IIIVO/JU), whereas the other strain was reactive to dietary cholesterol (AX/JU). The coefficient of inbreeding (F) >0.95 for both strains. Dietary cholesterol-reactive rabbits when compared with their non-reactive counterparts had a higher hepatic copper content. The consumption of a hypercholesterolemic diet decreased liver copper concentration (expressed in micro g/g dry weight) in both strains of rabbits, which was (in part) due to dietary-induced hepatomegaly. A decrease in the absolute hepatic copper content was found only in the dietary cholesterol-reactive inbred strain. It is discussed that differences in glucocorticoid levels may be responsible for the strain difference in liver copper content. The cholesterol effect on the hepatic copper content in the reactive strain might be caused by an increased bilirubin secretion.

Liver copper content of rats hypo- or hyperresponsive to dietary cholesterol.

The question addressed is whether cholesterol intake reduces the hepatic copper content in rats. For this purpose we have compared the hepatic copper content of two selected rat inbred strains after feeding the animals a control or a high fat, high cholesterol diet. One strain was dietary cholesterol resistant (SHR/OlaIpcv), whereas the other strain was susceptible to dietary cholesterol (BN-Lx/Cub). Dietary cholesterol-susceptible rats have a lower baseline hepatic copper content when compared with their resistant counterparts. The consumption of a hypercholesterolemic diet decreased the liver copper concentration (expressed in microg/g dry weight) to about the same extent in both strains. However, dietary cholesterol did not reduce the absolute (expressed as microg/whole liver) and relative (expressed as microg/whole liver/100 g body weight) copper store of rats. The decrease of liver copper concentration after the high fat, high cholesterol diet is probably not caused by a decrease in whole hepatic copper content, but rather due to dietary-induced hepatomegaly.

Quantitative trait loci influencing blood and liver cholesterol concentration in rats.

OBJECTIVE: The LEW/OlaHsd and BC/CpbU rat inbred strains differ markedly in blood and hepatic cholesterol levels before and after a cholesterol-rich diet. To define loci controlling these traits and related phenotypes, an F2 population derived from these strains was genetically analyzed. METHODS AND RESULTS: For each of the 192 F2 animals, phenotypes were determined, and genomic DNA was screened for polymorphic microsatellite markers. Significant quantitative trait loci (QTLs) were detected for basal serum cholesterol level on chromosome 1 (D1Rat335-D1Rat27: total population, lod score 9.6; females, lod score 10.3) and chromosome 7 (D7Rat69: males, lod score 4.1), for postdietary serum cholesterol level on chromosome 2 (D2Rat69: total population, lod score 4.4) and chromosome 16 (D16Rat6-D16Rat44: total population, lod score 3.3), for postdietary serum phospholipid level on chromosome 11 (D11Rat10: total population, lod score 4.1; females, lod score 3.6), and for postdietary serum aldosterone level on chromosome 1 (D1Rat14: females, lod score 3.7) and chromosome 18 (D18Rat55-D18Rat8: females, lod score 2.9). In addition, QTLs with borderline significance were found on chromosomes 3, 5 to 11, 15, and 18. CONCLUSIONS: QTLs involved in blood and/or hepatic cholesterol concentrations (or related phenotypes) in the rat were identified. This contributes to the value of the rat as an animal model in studies researching the role of cholesterol in the pathogenesis of atherosclerosis and other cholesterol-related diseases.