Retinoic Acid Signaling in Fatty Liver Disease

Abstract

Retinoic acid (RA) is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism. Through genomic and nongenomic actions, RA regulates a variety of physiological functions. Dysregulation of RA signaling is associated with many diseases. Targeting RA signaling has been proven valuable to human health. All-trans retinoic acid (AtRA) and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia (APL). Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease (NAFLD). In this review article, we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD. AtRA inhibits the development and progression of NAFLD via regulating lipid metabolism, inflammation, thermogenesis, etc.

Keywords: Retinoic acid; fatty acid oxidation; fatty liver disease; lipogenesis; obesity.

Fig. 1

Overview of vitamin A metabolism and RA signaling pathway. In the intestine, retinyl esters (REs) are hydrolyzed by RE hydrolase (REH) to form retinol. Retinal derived from β-carotene is reduced to retinol by retinaldehyde reductase. Retinol is esterified by lecithin-retinol acyltransferase (LRAT) to form REs, which are assembled into chylomicrons (CM) and secreted to the circulation. REs are uptaken by hepatocytes and are hydrolyzed to form retinol by hepatic REH. Retinol is secreted into the circulation and binds to the retinol-binding protein (RBP)/transthyretin (TTR) complex. The membrane protein STRA6 (signaling receptor and transporter of retinol STRA6) recognizes RBP and transports retinol into cells. In the cells, retinol is converted to retinal by retinol dehydrogenase (RDH), which is further converted to retinoic acid (RA) by retinaldehyde dehydrogenase (RALDH). All-trans-RA (AtRA) activates retinoic acid receptors (RARs), whereas 9-cis-RA activates retinoid X receptors (RXR). RAR and RXR form heterodimers and bind to retinoic acid elements (RAREs) to regulate gene transcription and a variety of pathways, e.g., development, growth, metabolism, inflammation, and tumorigenesis. RAR or RXR has three isoforms, α, β, and γ. Retinol may also be esterified to form REs by LRAT. About 80% of REs are stored in hepatic stellate cells (HSCs). Loss of REs from HSC may result in HSC activation. RA may be metabolized by CYP26A1, CYP26B1, or CYP26C1 to form 4-hydroxy-RA, 4-oxo-RA, etc.

Fig. 2

Regulation of the development of NAFLD by the RA/RAR signaling. Activation of the retinoic acid receptor (RAR) by RA inhibits the development of non-alcoholic fatty liver disease (NAFLD) likely via several pathways. Activation of RAR induces FA oxidation (FAO) and thermogenesis and inhibits fatty acid (FA) uptake, nuclear factor kappaB (NF-κB), and transforming growth factor beta (TGF-β), leading to a reduction in hepatic lipid accumulation, inflammation, and fibrogenesis. The role of RAR activation in the inhibition of de novo lipogenesis (DNL) remains to be further clarified.