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The effects of all-trans and 13-cis retinoic acid upon serum and liver lipids were investigated in Sprague-Dawley rats. Groups of rats were fed daily with 105, 210 and 315 micrograms/g diet of one of the retinoids for periods of up to 8 days. Other groups were injected intraperitoneally (I.P.) daily with retinoids at levels equivalent to the daily intake of rats receiving 105 or 210 micrograms of retinoid/g diet. All dietary concentrations of all-trans retinoic acid induced hypertriglyceridemia, however, only the highest dietary concentration of the 13-cis form caused this response. Injection of the all-trans form consistently increased serum triglycerides, while 13-cis retinoic acid did so in only one case. Retinoid-fed rats fasted for 6 hours before blood sampling demonstrated similar increases in serum triglycerides compared to their respective controls. Also, retinoid administration reduced serum retinol at all levels tested with the all-trans form appearing to be more potent. Growth and feed intake was somewhat reduced in rats receiving the highest level of all-trans retinoic acid. Liver analysis did not reveal fatty liver or alterations in phospholipid, cholesterol, or vitamin A content in any groups monitored. Our previous studies have shown induction of hypertriglyceridemia when rats were fed as low as 26 micrograms/g diet of all-trans retinoic acid. The current studies would indicate that feeding 315 micrograms/g diet of the 13-cis isomer was required to elicit a similar response.

Previous feeding experiments performed in our lab1,2 have shown that hypertriglyceridemia was induced by vitamin A in cholesterol-or non-cholesterol-fed rats. All-trans-retinoic acid (RA) was more potent than retinyl acetate in eliciting this response. A series of experiments have been subsequently performed to further investigate the effects of RA administration on lipid metabolism in the rat.Initially, the effects of all-trans-and 13-cis-RA were compared.3 Rats were intraperitoneally injected or fed, for up to 8 days, either 1500, 3000, or 4500 &day of either all-trans or 13-cis-RA. All levels of all-trans-RA induced hypertriglyceridemia; however, only the highest intake of the 13-cis form was effective. Injection of the all-trans form consistently increased serum triglycerides. Retinoid-fed rats fasted for 6 hr prior to blood sampling demonstrated similar increases in serum triglycerides compared to their non-fasted controls, suggesting that the hypertriglyceridemia was unrelated to altered intestinal metabolism. Additionally, retinoid administration was found to reduce serum retinol at all levels tested with the all-tpns form appearing to be more potent than the 1 3 4 s isomer.Three types of experiments were performed to characterize the hyperlipidemia. After feeding young adult male Sprague-Dawley rats supplemental retinoic acid (100 pg/g dry diet) for 3 days, and fasting them for 6-8 hr, the triglyceride, cholesterol, and phospholipid content of various serum lipoprotein fractions was determined. When compared to unsupplemented controls, both the VLDL and HDL fractions were found to harbor an elevated triglyceride content. While VLDL cholesterol and phospholipid content were also elevated in retinoic acidfed rats, total serum cholesterol and phospholipids were not statistically altered. Serum triglyceride accumulation was measured in an in vivo system, employing Triton WR 1339 blockade of serum lipoprotein clearance. RA feeding resulted in greater serum triglyceride accumulation compared to controls, suggesting increased triglyceride secretion from the liver. In vitro experiments have shown increased incorporation of lipid precursors into fatty acids and glycerides in rat liver isolates incubated with retinoic acid.4Since VLDL triglyceride is broken down by the lipoprotein lipase of extrahepatic tissues, the activity of the enzyme in several of these tissues was determined. Although perirenal adipose tissue lipoprotein lipase activity decreased by about 15% as a result of the intake of RA, more dramatic depressions of 76% and 64% were observed in red and white gastrocnemius muscle, respectively. Cardiac ventricular muscle lipoprotein lipase activity was not affected by retinoic acid feeding.In conclusion, triglyceride metabolism is altered in rats administered excess vitamin A in cholesterol-free or cholesterol-containing diets. Hypertriglyceridemia is evident in both the fasted and fed state. All-trans-retinoic acid appears to be more potent than either retinyl acetate or 13-cis-retinoic acid in elevating ...

This report describes a series of experiments that attempt to characterize the lipidemia accompanying retinoic acid administration. After feeding young adult male Sprague-Dawley rats, 1.2 Retinol Equivalents (R.E.) retinyl acetate plus supplemental retinoic acid (100 microgram/g dry diet) for three days and fasting for 6-8 hr, triglyceride, cholesterol, and phospholipid content of various serum lipoprotein fractions were determined. When compared to unsupplemented controls, both the serum very low density lipoprotein (VLDL) and the high density lipoprotein (HDL) fractions of the retinoic acid-fed rats were found to harbor an elevated triglyceride content. While VLDL cholesterol and phospholipid content were also elevated, total serum cholesterol and phospholipids were not statistically altered. The detergent Triton WR-1339 was used to depress serum triglyceride clearance in order to assess the effects of retinoic acid feeding on serum triglyceride levels. Triglyceride accumulation started earlier after Triton treatment and was greater when rats were fed 100 microgram/g retinoic acid for three days prior to testing. Red and white gastrocnemius muscle, cardiac ventricular muscle, and perirenal adipose tissue were removed from rats following retinoic acid feeding. Analysis of these tissues for lipoprotein lipase (EC 3.1.1.3) activity showed a decrease in adipose tissue, a large depression in both areas of gastrocnemius muscle and no change in cardiac muscle as a result of retinoic acid feeding.

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