Retinoic Acid Treatment Enhances Lipid Oxidation and Inhibits Lipid Biosynthesis Capacities in the Liver of Mice

Abstract

Vitamin A, mainly as retinoic acid (RA), is known to affect the development and function of adipose tissues. Treatment with RA reduces body weight and adiposity independent of changes in food intake in mice. Lipid metabolism in liver can have a major impact on whole body adiposity. The aim of this work was to investigate the effects of an in vivo treatment with RA on hepatic lipid metabolism in mice. Adult, standard diet-fed mice were treated with different doses of all-trans RA or vehicle (subcutaneous injection) for 4 days before sacrifice. Food intake and body weight changes during treatment were determined, as well as adiposity, liver composition, levels of circulating metabolites and lipoproteins and expression levels of key mRNA species in liver following sacrifice. RA treatment resulted in reduced body weight and adiposity, as expected. In the liver, RA treatment triggered an increase in the mRNA expression levels of peroxisome proliferator-activated receptor alpha, retinoid X receptor alpha, uncoupling protein 2, liver-type carnitine palmitoyltransferase 1, and carnitine/acylcarnitine carrier, and a reduction in the mRNA expression levels of sterol regulatory element binding protein 1c and fatty acid synthase. Consistent with the changes in gene expression, hepatic triacylglycerol content and circulating VLDL fraction were reduced and levels of circulating ketone bodies increased after RA treatment. These results point to a capacity of active vitamin A forms to shift liver lipid metabolism in vivo towards increased catabolism and reduced lipogenesis. These effects might contribute to the reduction of adiposity brought about by RA treatment.

All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes

“…The latter may include the white adipocytes themselves. In fact, ATRA treatment has been shown to increase the expression of genes related to oxidative metabolism, fatty acid oxidation, and thermogenesis in WAT depots ( 11,12 ), besides activating brown adipose tissue (BAT) ( 6, 7 ) and increasing lipid oxidation capacity in additional tissues such as skeletal muscle ( 12,13 ) and the liver ( 14 ). Moreover, cell-autonomous effects of ATRA in mature adipocytes reducing intracellular lipids, enhancing fatty acid oxidation, and triggering gene expression changes consistent with increased lipid turnover and oxidation have been described ( 15 ).…”

“…they were euthanized, as previously described ( 11,13,14 ). The other six animals were used as controls and injected the vehicle (100 l olive oil).…”

Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue

“…The literature suggests linkages between retinoid storage, metabolism, and actions and the development of fatty liver. Included in this literature are studies reporting ablation of hepatic retinoid receptor signaling resulting in hepatic steatosis ( 55 ), ablation of carotenoid-15,15 ′ -oxygenase (which abolishes retinoid production from ␤ -carotene) ( 56 ), studies of mice defi cient in CRBPIII ( 57 ), nutritional studies carried out in mice or rats (58)(59)(60)(61), studies of retinoid…”

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

“…Multiple studies have established that the treatment of RA, the active vitamin A metabolite, induces weight loss and attenuates insulin resistance in obesity and diabetes (6,7). One critical mechanism of the actions of RA is that activation of RAR may reduce hepatic lipid accumulation and normalize serum triglyceride levels (6,46). Unfortunately, the currently described RAR isotype knockout models demonstrate severe developmental defects; they display congenital malformations with the fetal and postnatal vitamin A deficiency syndrome (47), making it impossible to evaluate the impact of RAR on energy metabolism.…”