Review
Lipid metabolism in mammalian tissues and its control by retinoic acid

https://doi.org/10.1016/j.bbalip.2011.06.001Get rights and content

Abstract

Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

Highlights

► Treatment with all-trans retinoic acid reduces body fat and improves insulin sensitivity in mice by promoting fat mobilisation and catabolism. ► Retinoid-induced hypertriglyceridemia is, however, frequently encountered in humans and animal models. ► There is an intimate cross-talk between retinoid and lipid metabolism. ► Molecular mechanisms of retinoid effects on lipid metabolism are complex and not fully understood.

Introduction

Retinoids comprise vitamin A (retinol) analogs with or without biological activity as well as compounds that are not structurally related to retinol but elicit biological vitamin A or retinoid activity [1]. Retinoic acid (RA) is a major active cellular retinoid and an important regulator of gene expression. RA is synthesized intracellularly primarily from retinaldehyde (Rald), which itself can be produced from retinol or from provitamin A carotenoids such as β-carotene [1].

Among the many functions attributed to retinoids, their role in the control of lipid and energy metabolism – with potential implications for chronic disorders including obesity, diabetes, nonalcoholic fatty liver disease and atherosclerosis – is recognized [2], [3] and receiving an increasing attention in the latest years. Evidence has accumulated that specific retinoids, notably RA, impact on developmental and biochemical processes influencing mammalian adiposity including adipocyte differentiation (adipogenesis) and lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with RA [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15] or Rald [16] has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents. Moreover, genetic manipulation of various carotenoid/retinoid-metabolizing enzymes and transport proteins results in alterations in adiposity in mice [16], [17], [18], [19], [20], [21]. Remarkably, liver and adipose tissues, which are organs critically involved in retinoid storage and metabolism, are also critically involved in systemic lipid homeostasis.

Nevertheless, there have been controversial reports, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism, which may include both genomic and extragenomic actions, are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported effects of retinoids on different aspects of lipid metabolism in key tissues, focusing mainly on RA. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed.

Section snippets

Overview of lipid metabolism and its control

The liver plays a central role in the maintenance of systemic lipid homeostasis. Hepatocytes are responsible for the synthesis and secretion of very low-density lipoprotein (VLDL). The latter distributes lipids, primarily triacylglycerols, for storage and utilization by peripheral tissues, and gives rise to the low density lipoprotein particles. Hence, liver lipid metabolism conditions lipidemia and the availability of fuels for adipose tissue growth. Disturbances in lipogenesis, fat oxidation

Molecular basis of RA effects on mammalian lipid metabolism

RA modulates gene expression through multiple mechanisms (Fig. 2). Notably, RA isomers can bind to and activate two types of receptors of the nuclear receptor superfamily: the retinoic acid receptors (RARs), which in vitro bind both all-trans RA (atRA) and 9-cis RA with high affinity, and the retinoid X receptors (RXRs), which in vitro bind specifically 9-cis RA [1]. Both RARs and RXRs have three subtypes: α, β and γ. Whereas atRA is a major product of the intracellular oxidation of vitamin A,

RA effects on adiposity in vivo

Studies by independent groups including ours have shown that, in normal adult mice, treatment with atRA at different dosages and routes of administration reduces body weight and adiposity [4], [5], [6], [7], [8], [9], [12], [15] and enhances glucose tolerance and insulin sensitivity [7], [10] (Table 1). atRA treatment also ameliorated obesity, dyslipidemia, insulin resistance and hepatosteatosis in diet-induced obese mice [13], and similar results were obtained in a genetic mouse model of

RA effects on hepatic lipid metabolism

Changes in hepatic lipid metabolism leading to repartitioning of fatty acids away from triacylglycerol storage and towards oxidation appear to contribute to the anti-adiposity action of atRA in mice [12]. Thus, in our hands, atRA treatment resulted in an increase in the hepatic expression of genes encoding regulatory and metabolic proteins that favor fatty acid oxidation (PPARα, RXRα, CPT1, CAC, UCP2) and a dramatic decrease in the hepatic gene expression of lipogenic SREBP-1c and FAS [12].

RA effects on lipid metabolism in skeletal muscle

atRA treatment in mice was shown to enhance the capabilities for fatty acid oxidation, respiration and thermogenesis and to reduce the intramyocellular lipid content in skeletal muscle [11], [13], [112]. These findings suggest that effects on skeletal muscle metabolism contribute to the reduction of adiposity and the improved systemic insulin sensitivity seen in atRA-treated lean and obese mice.

Many genes related to oxidative metabolism have been reported being induced in skeletal muscle

RA effects in adipose tissues

Adipose tissues play an active role in retinoid homeostasis [135] and, reciprocally, retinoids and their related binding proteins and metabolizing enzymes are increasingly recognized to contribute to developmental and metabolic regulation in adipose tissues. In particular, multiple effects of RA on adipocyte biology have been demonstrated, including effects on the thermogenic capacity of brown adipocytes, the capacity for oxidative metabolism in white adipocytes, the secretory function of

Concluding remarks and prospective

Accumulated evidence indicates a role of vitamin A derivatives, and in particular atRA, in regulating energy balance and adiposity in adult animals through effects on lipid and energy metabolism. Studies in mice have shown that treatment with atRA can reduce body adiposity by enhancing fat mobilization and energy utilization systemically, in tissues including BAT, WAT, skeletal muscle and the liver (Fig. 3). RA also has a very interesting bioactivity as a potent suppressor of adipokines

Acknowledgments

The authors acknowledge the contribution of former and present members of the Laboratory of Molecular Biology, Nutrition and Biotechnology of the UIB and external collaborators to this line of research. They also acknowledge support from the Spanish Government (AGL2009-11277/ALI to A.P.) and the European Union (BIOCLAIMS project, FP7-244995, coordinated by A.P., and IDEFICS project, FP6-2004-FOOD-3-A016181-2). Our Laboratory is a member of The European Nutrigenomics Organization (NuGO). CIBER

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