Dietary fish oil up-regulates cholesterol 7alpha-hydroxylase mRNA in mouse liver leading to an increase in bile acid and cholesterol excretion.

To investigate the molecular events controlling reverse cholesterol transport, we compared gene expression of normal mouse liver to that of mice fed a long chain (LC) omega-3 fatty acid-enriched diet. Using cDNA microarrays, we assessed expression levels of 1176 genes, and we found that D-site binding protein (DBP) was three-fold increased in mice on a LC omega-3 fatty acid-rich diet compared to controls. DBP is known to increase transcriptional level of cholesterol 7alpha-hydroxylase (C7alpha), the rate-limiting enzyme for bile acid production and cholesterol excretion, and we found that C7alpha mRNA was also up-regulated by LC omega-3 fatty acids. Moreover, liver X receptor-alpha, another transcription factor up-regulating C7alpha, was three- to four-fold increased in liver of treated mice. On the other hand, we demonstrated that bile acid and cholesterol excretion were two-fold increased. These results show that LC omega-3 fatty acids control cholesterol metabolism in mice at a new endpoint.

n-3 FA increase liver uptake of HDL-cholesterol in mice.

In humans, diets rich in fish oil (containing n-3 FA) decrease the incidence of coronary artery diseases. This is thought to be caused by the induction in liver and skeletal muscle of genes involved in lipid oxidation, and to the repression in liver and adipose tissue of genes responsible for lipogenesis. n-3 FA are known to reduce the synthesis of FA and TG in the liver, resulting in a decrease of plasma concentrations of TG-rich lipoproteins. On the other hand, little is known of a possible effect of n-3 FA on HDL metabolism. To investigate this question, female C57Bl/6J mice were fed an n-3 FA-enriched diet for 16 wk. As expected from previous studies, we found that total cholesterol, TG, and phospholipids were reduced in the plasma of treated mice. We also found that HDL-cholesterol decreased after this treatment and that the in vivo fractional catabolic rate of HDL-cholesteryl ester was significantly higher in treated mice than in control mice fed a standard diet. Consistent with these results, treated mice exhibited increased uptake of HDL-cholesteryl ester in the liver. Moreover, quantitative reverse transcriptase-PCR analysis showed a two- to threefold increase in scavenger receptor B-1 gene expression. Taken together, these results suggest that an n-3 FA-enriched diet stimulates one step in the reverse cholesterol transport in mice, probably by increasing the amount of the scavenger receptor class B-1. These effects of n-3 FA on HDL metabolism may contribute to their beneficial effects on the vasculature.