Gene targeting in mice was used to investigate the unknown function of

No abstract

Our aim was to study the effects of increased dietary intake of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) on serum lipids and LDL fatty acid compositions. To this end, a controlled parallel study was conducted in 74 healthy normolipidemic men and women aged 19-43 y. Participants were randomly assigned to 1 of 3 interventions and consumed a total intake of 4.4 g/d ALA (ALA group), 2.2 g/d EPA (EPA group), and 2.3 g/d DHA (DHA group) for 6 wk. Fatty acid ethyl esters were incorporated into margarines, which replaced the participant's normal spread. The ALA, EPA, or DHA intake led to a significant enrichment of the LDL with the respective (n-3) fatty acid. In addition, LDL EPA contents in the ALA group increased by 36% (P < 0.05) with no changes in LDL DHA. The EPA intervention led to an additional enrichment with DHA (24%; P < 0.001), whereas the DHA intervention further increased the amount of EPA (249%; P < 0.001). ALA, EPA, or DHA intake did not affect fasting serum concentrations of total and LDL cholesterol, but fasting serum triacylglycerol concentrations significantly decreased in the EPA (-0.14 mmol/L) and DHA (-0.30 mmol/L) interventions and also in the ALA intervention (-0.17 mmol/L). DHA intake significantly increased serum HDL cholesterol, whereas no changes were found with ALA or EPA intake. In conclusion, the present data support the hypothesis that isolated dietary ALA, EPA, and DHA intakes lead to differential enrichment in LDL due to interconversion. Moderate amounts of ALA, EPA, and DHA are effective in improving lipid profiles of normolipidemic humans.

Hepatic up-regulation of sterol carrier protein 2 (Scp2) in mice promotes hypersecretion of cholesterol into bile and gallstone formation in response to a lithogenic diet. We hypothesized that Scp2 deficiency may alter biliary lipid secretion and hepatic cholesterol metabolism. Male gallstone-susceptible C57BL/6 and C57BL/6 Scp2(؊⁄؊) knockout mice were fed a standard chow or lithogenic diet. Hepatic biles were collected to determine biliary lipid secretion rates, bile flow, and bile salt pool size. Plasma lipoprotein distribution was investigated, and gene expression of cytosolic lipidbinding proteins, lipoprotein receptors, hepatic regulatory enzymes, and intestinal cholesterol absorption was measured. Compared with chow-fed wild-type animals, C57BL/6 Scp2(؊⁄؊) mice had higher bile flow and lower bile salt secretion rates, decreased hepatic apolipoprotein expression, increased hepatic cholesterol synthesis, and up-regulation of liver fatty acid-binding protein. In addition, the bile salt pool size was reduced and intestinal cholesterol absorption was unaltered in C57BL/6 Scp2(؊⁄؊) mice. When C57BL/6Scp2(؊⁄؊) mice were challenged with a lithogenic diet, a smaller increase of hepatic free cholesterol failed to suppress cholesterol synthesis and biliary cholesterol secretion increased to a much smaller extent than phospholipid and bile salt secretion. Scp2 deficiency did not prevent gallstone formation and may be compensated in part by hepatic up-regulation of liver fatty acid-binding protein. These results support a role of Scp2 in hepatic cholesterol metabolism, biliary lipid secretion, and intracellular cholesterol distribution.Cholesterol gallstone disease is characterized by a perturbation of the physical-chemical balance of cholesterol solubility in bile with an unphysiological cholesterol saturation. Hypersecretion of unesterified cholesterol into bile appears to represent the key molecular mechanism in the gallstone-susceptible C57L/J mouse (1, 2) and in humans (3). The plasma membrane contains up to 90% of total cell cholesterol (4), which implies that sterol trafficking in the cell is tightly controlled. Efforts to elucidate the complex molecular mechanisms of intracellular cholesterol transport suggested the contribution of vesicles (5) and carrier proteins such as sterol carrier protein 2 (Scp2) 1 (6) and the Niemann Pick type C1 (Npc1) protein (7).Scp2 is a soluble lipid transfer protein, which is capable of cholesterol transport in vitro (6,8,9). Although localized predominantly to peroxisomes, substantial amounts of Scp2 are present in cytosol (10, 11), suggesting that Scp2 may be involved in intracellular cholesterol transport in vivo. Indeed, several lines of evidence support this notion: (i) Scp2 antisense treatment of rats reduced and delayed biliary cholesterol secretion (6); (ii) diosgenin-induced hypersecretion of cholesterol into bile in rats was associated with increased hepatic Scp2 expression (6); (iii) adenovirus-mediated overexpression of Scp2 in mice led to increased biliary cholestero...

Objective: The objective of this study was to compare the effects of dietary monounsaturated fatty acids (MUFA), n-6 and n-3 polyunsaturated fatty acids (PUFA) on LDL composition and oxidizability. Design, setting and subjects: Sixty-nine healthy young volunteers, students at a nearby college, were included. Six subjects withdrew because of intercurrent illness and five withdrew because they were unable to comply with the dietary regimen. Interventions: The participants received a 2-week wash-in diet rich in saturated fatty acids (SFA) followed by diets rich in refined olive oil, rapeseed oil or sunflower oil for 4 weeks. Intakes of vitamin E and other antioxidants did not differ significantly between the diets. Results: At the end of the study, LDL oxidizability was lowest in the olive oil group (lag time: 72.6 min), intermediate in the rapeseed oil group (68.2 min) and highest in the sunflower oil group (60.4 min, P < 0.05 for comparison of all three groups). Despite wide variations in SFA intake, the SFA content of LDL was not statistically different between the four diets (25.8 -28.5% of LDL fatty acids). By contrast, the PUFA (43.5% -60.5% of LDL fatty acids) and MUFA content of LDL (13.7 -29.1% of LDL fatty acids) showed a wider variability dependent on diet. Conclusions: Enrichment of LDL with MUFA reduces LDL susceptibility to oxidation. As seen on the rapeseed oil diet this effect is independent of a displacement of higher unsaturated fatty acids from LDL. Evidence from this diet also suggests that highly unsaturated n-3 fatty acids in moderate amounts do not increase LDL oxidizability when provided in the context of a diet rich in MUFA.