The Dual Substrate Specificity of Aldehyde Oxidase 1 for Retinal and Acetaldehyde and its Role in ABCA1 Mediated Efflux

The high triglyceride, low high-density-lipoprotein (HDL) syndrome, visceral obesity, hypertension, and insulin resistance with or without hyperglycemia are the hallmarks of type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MS). Patients with T2DM or MS are at high risk for vascular disease, myocardial infarction and stroke [1]. Insulin resistance, as a major determinant of disease progression, is associated with TNF-α[2] and MCP-1 expression in visceral fat. MCP-1 expression results in macrophage accumulation in visceral fat and adipokine secretion [3]. Furthermore, insulin resistance is associated with impaired lipoprotein lipase (LPL) expression [4], enhanced secretion of apoB containing lipoproteins associated with hypertriglyceridemia [5] and activation of the renin/angiotensin/aldosterone system leading also to elevated blood pressure [6]. While the adipokine adiponectin seems not to be causally related to insulin resistance in healthy subjects [7] haplotypes in the adiponectin promoter are associated with increased risk of T2DM [8]. Obesity suppresses adiponectin secretion [9] and serum adiponectin correlates positively with HDL cholesterol [7] [10] and negatively with plasma triglycerides [7]. A key function of HDL in the process of reverse cholesterol transport is to transport cholesterol from peripheral tissues to the liver for biliary excretion [11]. Insulin resistance, metabolic overload and the dysregulation of adipokine and cytokine secretion promote nonalcoholic fatty liver disease (NAFLD) [12].

It was shown that mutations in the ATP-binding cassette transporter A1 (ABCA1) cause familial HDL-deficiency syndromes, highlighting ABCA1 as a major regulator of HDL metabolism [13] [14] [15]. Toxic products formed upon fatty acid oxidation and glycoxidation are increased in T2DM and MS and reduce ABCA1 protein stability [11]. Recently, aldehyde oxidase 1 (AOX1) was identified as an ABCA1 interacting protein affecting ABCA1 dependent phospholipid- and cholesterol-efflux (see article on page 781 in this issue). AOX1 expression is most prominent in the liver, as shown for humans [16], rats [17], and cattle [18]. The physiological function of AOX1 just starts to evolve. However, data from Tomita et al. indicate that AOX1 (EC 1.2.3.1) is identical to retinal oxidase [19], suggesting retinal as physiological substrate of AOX1. Both, the oxygen-dependent AOX1 and the cytosolic NAD⁺-dependent retinaldehyde dehydrogenase (EC 1.2.1.36) are capable of catalyzing the oxidation of retinal to retinoic acid (RA) [20]. The involvement of AOX1 in retinoid metabolism is further supported by chicken AOX1. This also possesses retinaldehyde oxidase activity [21]. The 9-cis RA and all-trans RA are both transcriptional modulators for retinoic acid receptor (RAR)/retinoid X receptor (RXR) target genes and recent data demonstrate the effect of retinoids on lipid efflux in macrophages [22]. A strong RA-dependent upregulation was observed for genes involved in cellular cholesterol homeostasis, including ABCA1 which is under transcriptional control of liver X receptor (LXR)/RXR.

The available data suggest AOX1 to be involved in ethanol-induced liver injury [23] and the generation of reactive oxygen species. AOX1 derived ROS are directly implicated in free radical damage in liver and brain during ethanol metabolism [24] [25] [26] [27] [28]. Alcohol dehydrogenase produces acetaldehyde and NADH from ethanol. Both are substrates for AOX1 and could lead to the formation of ROS in AOX1 expressing tissues [29] [30] [31]. A comparable two-step process is involved in the conversion of both ethanol and retinol into their corresponding acids [32].

Alcohol alters retinoid metabolism (I) by mobilizing vitamin A from the liver and thereby disrupting retinoid homeostasis (II) as competitive inhibitor of retinoic acid generation and (III) enhancer of vitamin A catabolism by inducing CYP2E1 [32]. Chronic and excessive alcohol intake not only leads to a higher risk of various cancers [32] but also alters lipid homeostasis. On one hand, moderate alcohol intake protects from coronary heart disease (CHD), probably because it has an advantage on high density lipoprotein (HDL) levels. On the other hand, heavy drinking was shown to exert adverse effects [33] and chronic alcohol consumption reduces HDL sphingomyelin content, thus impairing cholesterol efflux and uptake [34]. Interestingly alcohol consumption was also described to be associated with elevated triglyceride levels [35]. Alcohol may also affect factors related to the metabolic syndrome. However, no significant differences concerning alcohol consumption were found when comparing subjects with the metabolic syndrome and subjects with no risk factors for this syndrome [35].

In summary, AOX1 may affect plasma HDL levels by altering ABCA1 activity. AOX1 is capable of catalyzing the oxidation of both, retinal to RA and acetaldehyde to acetate and both substrates are supposed to compete for AOX1. This in turn may affect ABCA1 mediated function.

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