Hepatic retinol secretion and storage are altered by dietary CLA: common and distinct actions of CLA c9,t11 and t10,c12 isomers

Abstract

The maintenance of normal retinoid (vitamin A and its derivatives) homeostasis is required to support many crucial biological functions ( 1-3 ). All retinoids in animals are derived from the diet as preformed dietary vitamin A (retinyl esters, retinol, and very small amounts of retinoic acid) from animal products or as ␤ -carotene from vegetables and fruits ( 4 ). Within the intestine, ingested vitamin A is packaged into chylomicrons as retinyl ester regardless of its dietary origin ( 5 ). In the bloodstream, lipolysis of the chylomicrons generates smaller lipoprotein particles called chylomicron remnants, still retaining retinyl ester ( 6, 7 ). Approximately 75% of retinoids within chylomicron remants are cleared by the liver, which is the major site of vitamin A storage and metabolism ( 8-10 ). To meet tissue retinoid needs, the liver secretes retinol into the circulation bound to its sole specifi c transport protein, retinol-binding protein (RBP; also known as RBP4) ( 11,12 ). RBP is a 21 kDa protein with a single binding site for one molecule of all-trans -retinol. It is mainly, but not exclusively, synthesized within the hepatocytes. RBP circulates in the blood as a 1:1 molar complex with another serum protein, transthyretin (TTR), preventing retinol-RBP excretion by the kidney ( 11, 12 ). In the fasting circulation, retinol-RBP represents approximately 99% of all serum retinoids. Blood levels of retinol-RBP in both humans and animals are maintained very constant except in extreme cases of nutritional intake of vitamin A, protein, calories, and zinc or in response to hormonal factors, stress, and in certain disease states ( 11,13,14 ).Abstract Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid obtained from ruminant products. Previous studies in rats and pigs showed that a dietary equimolar mixture of c9,t11 and t10,c12 CLA isomers induces changes in serum and tissue levels of retinoids (vitamin A derivatives). However, the mechanism(s) responsible for these actions remain(s) unexplored. Given the numerous crucial biological functions regulated by retinoids, it is key to establish whether the perturbations in retinoid metabolism induced by dietary CLA mediate some of the benefi cial effects associated with intake of this fatty acid or, rather, have adverse consequences on health. To address this important biological question, we began to explore the mechanisms through which dietary CLA alters retinoid metabolism. By using enriched preparations of CLA c9,t11 or CLA t10,c12, we uncoupled the effects of these two CLA isomers on retinoid metabolism. Specifi cally, we show that both isomers induce hepatic retinyl ester accumulation. However, only CLA t10,c12 enhances hepatic retinol secretion, resulting in increased serum levels of retinol and its specifi c carrier, retinol-binding protein (RBP). Dietary CLA t10,c12 also redistributes retinoids from the hepatic stores toward the adipose tissue and possibly stimulates hepatic retinoid oxidation. Using mice lacking RBP, we also demonstrate that this ke...

Insights into the Molecular Mechanisms of the Anti-Atherogenic Actions of Flavonoids in Normal and Obese Mice

“…Real time RT-PCR protocol has been described previously [16]. Cyclophilin A and β-actin were used as housekeeping genes.…”

Short communication: Effect of conjugated linoleic acid on concentrations of fat-soluble vitamins in milk of lactating ewes

“…We hypothesized that the changes in lipid metabolism are accompanied by changes in the metabolism of fat-soluble vitamins in ruminants. Studies performed in mice (Ortiz et al, 2009;Chao et al, 2010;Chen et al, 2012) and pigs (Dugan et al, 2002) indicate that vitamin E and A concentrations in liver and body tissues are enhanced upon CLA feeding. Tocopherol concentrations in muscle of heifers have been also enhanced after feeding a rumen-protected CLA supplement (Schlegel et al, 2012b).…”

“…Similarly to TTP, RBP mRNA has been shown to increase in pig liver when feeding CLA (Dugan et al, 2002). Additionally, feeding the trans-10,cis-12-CLA isomer to mice increased liver retinol storage, liver retinol secretion, serum retinol and RBP levels, and adipose tissue retinyl esters (Ortiz et al, 2009). The mammary gland can incorporate retinoids from chylomicrons (via LPL) and from RBPbound retinol via specific receptors (O'Byrne et al, 2010;Alapatt et al, 2013;Li et al, 2014).…”

A single dose of c9,t11 or t10,c12 conjugated linoleic acid isomers perturbs vitamin A metabolism in mice

“…Interestingly, previous studies from our laboratory have demonstrated that chronic intake of conjugated linoleic acid (CLA) interferes with the maintenance of serum, liver and adipose retinoid homeostasis [14]. …”

“…By using a gavage dose of radiolabeled retinol containing either one of two CLA isomers, i.e. CLA t10,c12 or c9,t11, we show that, in contrast to chronic CLA intake [14], both isomers rapidly stimulate hepatic retinoid accumulation as well as hepatic secretion of retinol likely bound to RBP. We also provide some evidence suggesting that dietary CLA intake enhances intestinal absorption of recently ingested vitamin A.…”