The Regulation of a Regulator of Plasma Triglycerides

ApoA-V is involved in the regulation of plasma triglyceride levels. Thus, human apoA-V transgenic mice have lower triglyceride levels than controls, whereas the knockouts have increased levels.1 Because hypertriglyceridemia is an independent risk factor for the development of atherosclerosis and cardiovascular diseases, elucidation of the mechanism behind the regulation of apoA-V is of great importance. Expression of apoA-V is increased by interaction of the heterodimer PPAR (peroxisome proliferator-activator receptor)/RXR (retinoid X receptor) with a “Direct Repeat”1 (DR1) sequence in the apoA-V promoter.3,4 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Genoux et al5 show that the retinoid-related orphan receptors alpha (ROR ) 1 and 4 are also involved in the regulation of the apoA-V gene by interaction with the DR1 binding site. This interaction occurs with the human gene but not in mice, which is logical because the motive is not conserved in mice. ROR has been crystallized with cholesterol in the binding site.6 Also, cholesterol stabilizes ROR , and depletion of cellular cholesterol by statins has been shown to modulate the transcriptional activity of ROR .6 For a review, see Boukhtouche et al.7 However, it remains to be clarified whether cholesterol is a physiological ligand for ROR . The connection between apoA-V and ROR opens up interesting possibilities, because ROR has been shown to prevent atherosclerosis (see Boukhtouche et al7 for review). Thus, both the knockout mice and the natural knockout, the so-called staggerer mice, have an increased frequency of atherosclerosis (see Boukhtouche et al7 for review). ROR has previously been shown to regulate the expression of apoA-I, which may be one of the reasons why the receptor prevents atherosclerosis. Moreover, it has been shown to inhibit inflammatory responses in smooth muscle cells by transcriptional regulation of the IB gene, which codes for the inhibitor of NFB transcription factor activity. Thus, ROR interferes with the signaling pathway of NFB (see Boukhtouche et al7 for review). It should also be kept in mind that ROR appears to have an important role in lipid homeostasis in skeletal muscle.8 Such an effect may affect the insulin sensitivity, thereby giving rise to a reduced incidence of atherosclerosis. Because hypertriglyceridemia is an independent risk factor for atherosclerosis, the observation that ROR regulates apoA-V5 may indicate that this protein must also be taken into account when explaining the antiatherogenic effect of ROR . What is the role of apoA-V in the regulation of plasma triglyceride levels? Two mechanisms have been proposed: (1) that apoA-V influences the removal of triglycerides from plasma; and (2) that apoA-V influences the secretion of VLDL. Degradation of plasma triglycerides is catalyzed by the enzyme lipoprotein lipase (LPL). This enzyme is mainly expressed in adipose tissue and muscle, and acts bound to the proteoglycans on the endothelial cells of the vasculature in these tissues. The enzyme is activated by apoC-II, whereas apoC-III has been shown to inhibit it (see, for example, van Dijk et al9 for review). Based on results in transgenic mice it was concluded that apoA-V induced both an increase in lipolysis, through the increase in the LPL activity, and an elevated removal of VLDL particles.10 Using adenovirus-mediated gene transfer of apoA-V, it has been shown that the protein decreased the hypertriglyceridemia induced both by an intravenous and an intragastric fat load.11 Thus, the protein not only influences the turnover of VLDL, but also that of chylomicrons. These studies also showed that apoA-V increased the LPL activity in vitro.11 However, other authors have failed to observe an effect of apoA-V on the LPL activity12 unless proteoglycans are present. These observations led the authors to speculate that apoA-V guides chylomicrons and VLDL to proteoglycan-bound LPL. Taken together, the results from studies in mice indicate that apoA-V can influence the hydrolysis of plasma triglycerides (for review, see also van Dijk et al9). There are somewhat divergent opinions about the exact mechanism, however. Recently, apoA-V was investigated in human plasma.13 The results demonstrated that the apolipoprotein was associated with lipoproteins; in addition to VLDL, also with HDL and chylomicrons, but not with LDL. The distribution of apoA-V is actually very similar to that of apoC-III, and it has been suggested that these two proteins influence the triglyceride degradation in opposite directions: apoA-V stimulating the LPL and apoC-III inhibiting it. Interestingly, there have From the Wallenberg Laboratory, University of Göteborg, Sahlgrenska University Hospital, Göteborg, Sweden. Correspondence to Sven-Olof Olofsson, Wallenberg Laboratory, University of Göteborg, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2005;25:1097-1099.) © 2005 American Heart Association, Inc.