Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders

Abstract

Much evidence has accumulated in the literature over the last fifteen years that indicates vitamin A has a role in metabolic disease prevention and causation. This literature proposes that vitamin A can affect obesity development and the development of obesity-related diseases including insulin resistance, type 2 diabetes, hepatic steatosis and steatohepatitis, and cardiovascular disease. Retinoic acid, the transcriptionally active form of vitamin A, accounts for many of the reported associations. However, a number of proteins involved in vitamin A metabolism, including retinol-binding protein 4 (RBP4) and aldehyde dehydrogenase 1A1 (ALDH1A1, alternatively known as retinaldehyde dehydrogenase 1 or RALDH1), have also been identified as being associated with metabolic disease. Some of the reported effects of these vitamin A-related proteins are proposed to be independent of their roles in assuring normal retinoic acid homeostasis. This review will consider both human observational data as well as published data from molecular studies undertaken in rodent models and in cells in culture. The primary focus of the review will be on the effects that vitamin A per se and proteins involved in vitamin A metabolism have on adipocytes, adipose tissue biology, and adipose-related disease, as well as on early stage liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Keywords: Adipocyte; Insulin Resistance; Non-Alcoholic Fatty Liver Disease (NAFLD); Obesity; Retinoic Acid; Retinoid; Type 2 Diabetes.

Figure 1.. Chemical structures for vitamin A metabolites mentioned in the text.

By definition, vitamin A is all-trans-retinol. There are a number of different retinyl esters found within the body, all of these possess long chain acyl groups. The most abundant retinyl esters in the body are retinyl palmitate, retinyl sterate, retinyl oleate, and retinyl linoleate, accounting for greater than 95% of the body’s total retinyl ester pool. Short chain retinyl esters like retinyl acetate do not occur in nature and are found only in food supplements. All-trans-β-carotene is the prototypic provitamin A carotenoid that can be enzymatically converted to vitamin A.

Figure 2.. Generalized metabolic scheme for the major steps important to vitamin A metabolism.

All vitamin A is derived from the diet either as preformed vitamin A (predominantly retinyl esters and retinol) or as provitamin A carotenoids such as β-carotene. Once internalized, vitamin A (retinol) can be converted to its retinyl ester storage forms primarily through the actions of lecithin:retinol acyltransferase (LRAT), but also in some instances by diacylglycerol acyltransferase 1 (DGAT1). The stored retinyl esters undergo hydrolysis through the actions of a retinyl ester hydrolase (REH). The molecular identities of physiologically important REHs remain to be elucidated. Retinol can be oxidized to retinaldehyde primarily through the actions of retinol dehydrogenase 10 (RDH10), although other enzymes have also been proposed to catalyze this oxidation in vivo. A number of enzymes are able to catalyze the reverse reaction, the reduction of retinaldehyde to retinol. These enzymes are referred to as retinaldehyde reductases (RalRs). Retinol can also be secreted from cells/tissues into the circulation bound to retinol-binding protein 4 (RBP4). The concentration of retinol that is present within the blood is in the low μM range. Retinaldehyde undergoes oxidation to retinoic acid, the vitamin A form needed for transcriptional regulation. Retinoic acid formation is catalyzed by one of three aldehyde dehydrogenase, ALDH1A1, ALDH1A2 or ALDH1A3. The concentration of retinoic acid present in cells and tissues is in the low nM range. Retinoic acid can undergo further oxidative metabolism catalyzed by CYP26A1, CYP26B1 or CYP26C1 forming a number of oxidized products. Although some of these oxidized metabolites have been proposed to have transcriptional modulatory activity, these metabolites are destined predominantly for elimination from the body.

Figure 3.. Depiction of RBP4 immunomodulatory actions locally within and how this gives rise to insulin resistance.

RBP4 synthesized by adipocytes (A) (or possibly arriving from the circulation) activates resident adipose tissue macrophages (M) and dendritic/antigen presenting cells (APC). Through a JNK-dependent pathway, this induces proinflammatory cytokine secretion (TNFα and IL-1β) from macrophages and expression of major histocompatibility complex class II (MHCII) molecules as well as costimulatory molecules. The proinflammatory molecules and cytokines directly contribute to adipose tissue inflammation and insulin resistance. The activated antigen presenting cells induce CD4 T cell proliferation and Th1 polarization increasing levels of TNFα and IFN-γ which further stimulate adipose tissue macrophages bringing about increased local inflammation and systemic insulin resistance. Adapted from Moraes-Vieira et al. (2014).

Figure 4.. Diagramatic providing a summary of how STRA6 acts to mediated RBP4-induced metabolic disease.

The process is depicted as involving six steps. The mechanism links vitamin A uptake by STRA6-expressing cells with a signaling cascade that regulates expression of multiple STAT target genes. Step 1 commences with the binding of holo-RBP4 to its binding site on the extracellular surface of STRA6. STRA6 is primed with apo-RBP1 bound to its intracellular side. In Step 2 retinol is released by RBP4 and traverses through a pore in STRA6. The movement of retinol is proposed to trigger the phosphorylation of JAK2. Phospho-JAK2 initiates Step 3 which results in the phosphorylation of STRA6 and the frees RBP1 to be released from STRA6. This is followed by Step 4 where holo-RBP1 is released from STRA6 and STAT3 or STAT5 are recruited and undergo activation through phosphorylation by phospho-JAK2. In Step 5, holo-RBP1 delivers retinol to LRAT which converts the retinol to retinyl ester releasing apo-RBP1. This occurs concurrently with the movement of activated phospho-STAT3/5 to the nucleus where it induces expression of STAT target genes including suppressor of cytokine signaling 3 (SOCS3). This results in an inhibition of insulin signaling and PPARg activation. Step 6 involves the binding of apo-RBP1 to STRA6 and the dephosphorylation of JAK2 and STRA6, priming STRA6 for another round of binding with holo-RBP4. Figure 4 was adapted from [(Noy 2016b)].